Mitochondrial Respiratory Complexes

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Received: 17 November 2021 | Accepted: 23 August 2022
DOI: 10.1002/jcp.30869
REVIEW ARTICLE
Mitochondrial respiratory complexes: Significance in human

mitochondrial disorders and cancers
Kunwar Somesh Vikramdeo1,2 | Sarabjeet Kour Sudan1,2 | Ajay P. Singh1,2,3 |

Seema Singh1,2,3 | Santanu Dasgupta1,2,3
1
Department of Pathology, Mitchell Cancer
Institute, University of South Alabama, Abstract
Mobile, Alabama, USA
Mitochondria are pivotal organelles that govern cellular energy production through
2
Department of Pathology, College of
Medicine, University of South Alabama,
the oxidative phosphorylation system utilizing five respiratory complexes. In
Mobile, Alabama, USA addition, mitochondria also contribute to various critical signaling pathways
3
Department of Biochemistry and Molecular including apoptosis, damage‐associated molecular patterns, calcium homeostasis,
Biology, University of South Alabama, Mobile,
Alabama, USA lipid, and amino acid biosynthesis. Among these diverse functions, the energy
generation program oversee by mitochondria represents an immaculate orchestra-
Correspondence
tion and functional coordination between the mitochondria and nuclear encoded
Santanu Dasgupta, Department of Pathology,
College of Medicine, Cancer Biology Program, molecules. Perturbation in this program through respiratory complexes' alteration
Mitchell Cancer Institute, University of South
results in the manifestation of various mitochondrial disorders and malignancy,
Alabama, 1660 Springhill Avenue, Mobile,
AL 36604, USA. which is alarmingly becoming evident in the recent literature. Considering the clinical
Email: [email protected]
relevance and importance of this emerging medical problem, this review sheds light
Funding information on the timing and nature of molecular alterations in various respiratory complexes
Seema Singh, Grant/Award Numbers: and their functional consequences observed in various mitochondrial disorders and
CA204801, CA231925; Ajay Pratap Singh,
Grant/Award Number: CA224306
human cancers. Finally, we discussed how this wealth of information could be
exploited and tailored to develop respiratory complex targeted personalized
therapeutics and biomarkers for better management of various incurable human
mitochondrial disorders and cancers.
KEYWORDS
ATP, cancer, genetic disorders, mitochondria, oxidative phosphorylation (OXPHOS), respiratory
complexes
1 | INTRODUCTION (OXPHOS) system involves the generation of NADH and FADH2

during the tricarboxylic acid (TCA) cycle, which are then fed into
Mitochondria are important cytoplasmic organelles, which are electron transport chain (ETC) comprising of five respiratory
involved in energy production. In addition, they also regulate multiple complexes (RCs) situated in the inner membrane of mitochondria.
other signaling pathways including apoptosis, damage‐associated As depicted in Figure 1, the OXPHOS functions through unique
molecular patterns (DAMPs) and calcium homeostasis, fatty acid, and coordination of both nuclear DNA (nDNA) and mitochondrial DNA
amino acid biosynthesis signaling (Grazioli & Pugin, 2018; Nowinski (mtDNA) encoded RC proteins. While the mtDNA encoded RC
et al., 2020; Rizzuto et al., 2012; Spinelli & Haigis, 2018; Vyas et al., molecules are transcribed and translated by the mitochondria, the
2016). ATP formation through the oxidative phosphorylation nDNA transcribed OXPHOS genes are translated in the cytosol and
Kunwar Somesh Vikramdeo and Sarabjeet Kour Sudan equally contributed to this study.
J Cell Physiol. 2022;237:4049–4078. wileyonlinelibrary.com/journal/jcp © 2022 Wiley Periodicals LLC. | 4049

10974652, 2022, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jcp.30869 by Conricyt Fondo Institucional Del Conacyt, Wiley Online Library on [06/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4050 | VIKRAMDEO ET AL.
F I G U R E 1 Nuclear‐mitochondrial genes synchronization. Mitochondrial respiratory complex function is maintained by both nDNA and
mtDNA encoded genes. The transcripts of the nDNA‐encoded respiratory complex subunits are translated in the cytoplasm and imported in the
mitochondria through the mitochondrial TOMM/TIMM import machinery. Only 13 genes of the various respiratory complex (I: ND1, ND2, ND3,
ND4, ND4L, ND5, and ND6; III‐CYTB, IV: COXI, COXII, COXIII, and V: ATP6 and ATP8) are mitochondria encoded (in bold). The noncoding rRNA
and 22 tRNA genes are involved in the translation of the mtDNA encoded transcripts. The displacement loop (D‐loop, in red) is the critical
noncoding mtDNA region where replication initiates. The D‐loop region contains promoters for the transcription of RNA from the two mtDNA
strands. The guanine‐rich heavy strand (H) is transcribed from the PH promoter, whereas the light strand (L) is transcribed from the PL promoter.
The DNA polymerase‐mediated replication of the heavy strand starts from the OH replication origin, eventually exposing the OL origin, thereby
allowing replication of the light strand. IMM, inner mitochondrial membrane; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; OMM, outer
mitochondrial membrane; TIMM, translocase of the inner mitochondrial membrane; TOMM, translocase of the outer mitochondrial membrane
imported in the mitochondria through the mitochondrial protein much easier to detect because of the high copy number in the cells
import machinery, composed of translocases of the outer and inner (Chatterjee et al., 2011; Ferguson et al., 2015; Hertweck &
mitochondrial membrane (TOMM and TIMM) (Neupert & Herrmann, Dasgupta, 2017).
2007). Notably, in addition to the OXPHOS molecules, all other Imbalance in OXPHOS system can occur due to alterations in
nDNA encoded proteins (~1500), which function in mitochondria, are either of nDNA and mtDNA encoded RC genes. Earlier studies
also imported through the TOMM/TIMM machinery, which under- speculated that mtDNA mutations make up for only a small portion of
lines a fine nuclear‐mitochondria orchestration to ensure proper functional anomaly in various RCs. However, subsequent studies
mitochondria functioning. have shown that mtDNA mutations, in fact, account for a much
Human mitochondria are maternally inherited and harbor their higher number of cases of RC alterations, especially those belonging
own genome (16.5 kb double‐stranded closed circular DNA). The to RCI (Moslemi et al., 2008; Naess et al., 2009; Shanske et al., 2008;
human mitochondrial genome contains 37 genes that encode for 12S Ugalde et al., 2004). These alterations in mtDNA encoding different
and 16S rRNAs, 22 tRNAs, and 13 protein subunits of the OXPHOS RC subunits are responsible for several human diseases, including
system (Taanman, 1999) (Figure 1). Each cell contains hundreds of cancer (Chatterjee et al., 2011; Ferguson et al., 2015; Hertweck &
copies of the mtDNA, and nearly all these mtDNAs are identical at Dasgupta, 2017). Indeed, the manifestation of many mitochondrial
birth (homoplasmic or wild type). However, due to environmental or diseases involve both mitochondrial and nuclear genomes with all
genotoxic damages, mutations occur in the wild‐type mtDNA copies, possible inheritance patterns such as maternal, X linked, de novo,
causing an imbalance in the homoplasmic state. This condition is autosomal recessive or autosomal dominant trait (Craven et al.,
known as heteroplasmy, where mutated mtDNA copies coexist with 2017). In subsequent sections, we discuss the structure, evolution,
the wild‐type mtDNA (Figure 2). Under the selection pressure, the and functions of mitochondrial RCs. Besides, we emphasize the role
cells may continue to maintain either a heteroplasmic state with of RC alterations in various mitochondrial disorders and cancers. This
increased mutant to wild‐type mtDNA (higher heteroplasmy state) or timely discussion should instigate further research in the direction of
a homoplasmic state harboring the mutant mtDNA copies only. The targeting mitochondria for the prevention and therapy of OXPHOS‐
mutation rate in mtDNA is nearly 10 times higher than nDNA and associated mitochondrial diseases and human cancers.
VIKRAMDEO ET AL. | 4051
F I G U R E 2 The mtDNA homoplasmy and

heteroplasmy. Cells with wild‐type mtDNA copies
(blue) maintain a homoplasmic state at birth.
However, environmental or genotoxic damages
could introduce mtDNA mutation in the
mitochondria, thereby generating a heteroplasmic
condition with an admixture of both wild‐type
and mutant (red) mtDNA. During development
and progression of a disease, the mitochondria
may attain a greater heteroplasmic state with
increased mutant:wild‐type mtDNA ratio or a state
of homoplasmy harboring mutant mtDNA copies
only. mtDNA, mitochondrial DNA.
2 | R C M A C H I N E R Y AN D T H E OX P H O S translocation and UbQ binding are thought to perform by mtDNA‐

JO URNEY encoded seven subunits (Friedrich & Böttcher, 2004), whereas the
remaining nuclear subunits are imported into the mitochondria
Mitochondria are the “powerhouse” of the cell as they generate ATP (Hoogenraad et al., 2002; Janssen et al., 2006; Stojanovski et al.,
via OXPHOS complexes, located on the inner membrane of the 2003). Seven nuclear‐encoded subunits constitute the core part in
mitochondria. This transfer of electrons generates a proton gradient, the peripheral arm of RCI namely NDUFV1, NDUFV2, NDUFS1,
which is then utilized by the ATP synthase (complex V) to produce NDUFS2, NDUFS3, NDUFS7, and NDUFS8. These are involved in
ATP from ADP and inorganic phosphate. All the RCs involved in the catalysis of oxidation of NADH and electron transfer (Lazarou
OXPHOS are discussed below in the subsections. et al., 2009). These core subunits contain three cofactors: A flavin
mononucleotide (FMN) molecule; 7‐9 FeS clusters (2Fe‐2S)N1b, (4Fe‐
4S)N3, (4Fe‐4S)N4, (4Fe‐4S)N5, (4Fe‐4S)N6a/b, and (4Fe‐4S)N2 clusters
2.1 | RCI (Gai et al., 2015; Sazanov & Hinchliffe, 2006; R. Z. Zhao et al., 2019)
and the last electron‐accepting iron‐sulfur cluster (N2 cluster), that
RCI, also known as NADH: ubiquinone oxidoreductase catalyzes the delivers electrons to UbQ binding sites (Hunte et al., 2010). Q unit
first step of the mitochondrial ETC (Saraste, 1999) (Figure 3a). RCI is consists of NDUFS2, NDUFS3, NDUFS7, and NDUFS8 subunits
the largest multisubunit enzyme complex in the ETC. Its important (Vogel et al., 2007). The remaining nDNA subunits are known as
role is to feed electrons from the soluble carrier molecule NADH into “supernumerary” subunits and are not involved in RCI enzymatic
the respiratory chain and transfer them to a quinol in the membrane. activity (Hirst et al., 2003). It was later suggested that these subunits
The energy released in the electron transfer reaction is utilized for help in RCI biogenesis and support the structural stability of RCI
pumping four protons from the matrix into the cristae lumen (Carroll et al., 2003; Friedrich & Böttcher, 2004).
(Kühlbrandt, 2015; Lenaz et al., 2006). Structural and phylogenetic
studies revealed that the RCI enzyme consists of three modules: a
dehydrogenase module (N) that accepts electrons from NADH, a 2.2 | RCII
hydrogenase‐like module (Q) that delivers electrons to ubiquinone
(UbQ), and a deeply embedded transporter module (P) that pumps RCII is also known as succinate dehydrogenase (SDH) or succinate:
protons across the inner membrane (Friedrich & Scheide, 2000; ubiquinone oxidoreductase (SQR). It consists of four subunits, SDHA,
Mathiesen & Hägerhäll, 2002). Analysis of bovine and human mt SDHB, SDHC, and SDHD encoded by the nucleus. The RCII does not
revealed that the RCI is a very large enzyme, consisting of 45 harbor any mtDNA encoded subunit. RCII acts bifunctionally, that
subunits with a mass of 1000 KDa (Kampjut & Sazanov, 2020; is, in the ETC and the TCA cycle (Ackrell, 2000; Cecchini, 2003;
Sharma et al., 2009; Zhu et al., 2016). Seven subunits are encoded by Saraste, 1999). The SDH oxidizes succinate to fumarate in TCA cycle
the mitochondrial genome and are named ND1, ND2, ND3, ND4, (Cecchini, 2003). The SQR activity involves the transfer of electrons
ND4L, ND5, and ND6 (Chomyn et al., 1985, 1986). Proton from succinate to UbQ. Despite showing structural and functional
F I G U R E 3 Mitochondrial respiratory chain complexes. (a) Diagrammatic representation of the electron transport chain and the OXPHOS
systems. ETC consists of five complexes from CI to CV and three of these are proton pumps. Besides, it has two intermediary substrates
(coenzyme Q and cytochrome c). Dotted line shows the flow of electrons in the chain. Electrons move from complex I and II to CoQ molecule.
The reduced CoH2 passes electrons to the CoQH2–cyt c reductase complex. The peripheral cyt c diffuses in the intermembrane space, and
transports electron from CoQH2–cyt c reductase complex to the cyt c oxidase complex and finally to O2. The NADH, H+, and FADH2 produced
are oxidized further by the components of mitochondrial respiratory chain to generate an electrochemical gradient of protons, that enters into
F1F0‐ATP synthase (CV) and forms ATP. (b) Diagrammatic representation of the super complexes; respiratory chain complexes associates with
each other to form supercomplexes. CI forms a complex with CIII and CIV (SCI + III2 + IV). CI associates with CIII (SCI + III2), CIII with CIV
(SCIII2 + IV). CIV and CV also forms a dimer supercomplex (SCIV2 and SC V2). CoQ, coenzyme Q; cyt c, cytochrome c; ETC, electron transport
chain; OXPHOS, oxidative phosphorylation.
homology to RCII, bacterial fumarate reductase functions opposite Oxidation of ubiquinol at RCIII requires two electrons from RCI and
and catalyzes the reduction of fumarate to succinate during RCII. It has been established that there are two different reaction sites
anaerobic respiration (Hägerhäll, 1997; Maklashina et al., 1998; in complex III namely quinone reduction (QN) and quinol oxidation (QP)
Yankovskaya et al., 2003). Structure of RCII revealed that SDHC and sites. At the QP site, the two electrons from an ubiquinol (QH2) take
SDHD subunits are present within the mitochondrial inner membrane different paths. The first electron is transferred to Reiske iron–sulfur
(MIM) and has a short segment that extends toward the intermem- center protein (RISP) which is then translocated to Cyt1 and
brane space and SDHA and the SDHB subunits are projected consequently to cyt c. This electron produces unstable radical
toward the matrix (F. Sun et al., 2005). Unlike other RC complexes, ubisemiquinone (Q•‐), which then donates its unpaired electron to
RCII is not associated with the translocation of protons in ETC (R. Z. oxygen and generates superoxide (Matsuno‐Yagi & Hatefi, 1999). The
Zhao et al., 2019). second electron causes the reduction of ubiquinone/ubisemiquinone
(Q/SQ−) at the QN site. The Q and QH2 at the QN and QP sites are in
free exchange with those present in the membrane‐bound quinone/
2.3 | RCIII quinol pool. In general, it has been observed that the unpaired electron
of ubisemiquinone is transported to the two heme groups of Cytb
RCIII has a central position in the respiratory chain and is involved in (Heme bL and Heme bH). Ubisemiquinone transfers its electron to Heme
ubiquinol oxidation and cytochrome c (cyt c) reduction. It is a bL and form ubiquinone. Heme bL then donates an electron to Heme bH
symmetrical dimer and consists of 11 subunits per monomeric unit that results in the reduction of another molecule of ubiquinone again
(H. Schägger et al., 1986). The catalytically active subunits present in producing ubisemiquinone. One Q‐cycle is followed by the second one
RCIII are cytochrome b (bL and bH), cytochrome c1 (Cyt1), and (2Fe‐ that results in the oxidation of two molecules of ubiquinol, reduction of
2S) cluster (Xiaohang & Trumpower, 1986). During the UbQ‐cycle, two molecules of cyt c and reduction of one molecule of ubiquinone
mitochondrial complex III generates superoxide (J. Sun & Trumpower, (Chandel, 2010).
2003). RCIII has 10 or 11 diverse subunits in yeast and mammals,
respectively (Hunte et al., 2000; Iwata et al., 1998). Among these
subunits, three are catalytic: cytochrome b (Cytb), Cyt1, and the 2.4 | RCIV
Rieske‐FeS protein Rip1 (Iwata et al., 1998). In eukaryotes, all RCIII
subunits are encoded by nDNA except Cytb that is encoded by the RCIV or cyt c oxidase (COX), catalyzes the electron transfer from
mtDNA. reduced cyt c to terminal acceptor, O2, and generates water. In
mammals, four redox‐active metal centers are present in 13 different known as respirasome as it consists of all components important to
subunits of RCIV. These centers include CuA, heme a (Fea), and a transfer electrons from NADH to O2 (Letts & Sazanov, 2017;
binuclear center composed of heme a3 (Fea3) and CuB (Kadenbach & Schägger & Pfeiffer, 2000).
Hüttemann, 2015; Tsukihara et al., 1996). cyt c is a mobile electron Other studies identified the involvement of two regions linking
carrier and is lightly attached toward the outer surface of the inner direct association between RCI and RCIII. The first region comprises an
mitochondrial membrane. This attachment helps it to interact with interaction between RCI subunits NDUFA11 and NDUFB4 and
the Cyt1 of RCIII and to accept electrons (Shimada et al., 2017). UQCRQ on RCIII. The other one comprises interaction of NDUFB9
Reduced cyt c interacts with RCIV by electrostatic interactions and and NDUFB4 on RCI with UQCRC1 and UQCRFS1 on RCIII (Letts et al.,
transfers electrons to CuA center from where the electrons move 2016; Wu et al., 2016). A smaller proportion of RCI has also forms a
toward the subunit I and forms H2O (Shimada et al., 2017). Four complex with CIII2 (SCI + III2) (Schägger & Pfeiffer, 2001). Besides, CIII2
electrons move simultaneously from cyt c and bind dioxygen. Four of forms a SC with RCIV (SCIII2 + IV) (Schägger & Pfeiffer, 2000). Finally,
eight protons are used to form two water molecules, and the CIV and CV can also form dimers (CIV2 and CV2) (Allegretti et al., 2015;
remaining four are pumped into the inner membrane space (IMS) of Tsukihara et al., 1996). It is believed that supernumerary subunits in the
mitochondria (Wikstrom, 1977). RCI are responsible for the formation of different types of SC (Stroud
et al., 2016). In addition, studies demonstrated that phospholipids,
especially cardiolipins, are also crucial for supercomplex formation
2.5 | RCV (Bazán et al., 2013; Pfeiffer et al., 2003).
The formation of different types of SC also depends on the
RCV or F1F0 ATP synthase contains two important functional metabolic demands of cells (Greggio et al., 2017; Schägger & Pfeiffer,
domains: F0 and F1. The F0 domain is situated toward the 2000). Overall, the SCs contribute in various ways: (1) transfers
mitochondrial membrane and consists of c‐ring subunit, a, b, d, F6 electrons from NADH to O2 (Schägger & Pfeiffer, 2000; Shinzawa‐Itoh
subunits, oligomycin sensitivity conferring protein (OSCP), and other et al., 2016), (2) reduce reactive oxygen species (ROS) production
the accessory subunits e, f, g, and A6L (Dickson et al., 2006; during electron transport (Lopez‐Fabuel et al., 2016; Maranzana et al.,
Jonckheere et al., 2012). The b, d, F6, and OSCP subunits form the 2013), and (3) enhance the electron transfer efficiency of the Q and cyt
peripheral stalk and is present on one side of the complex, whereas c (Blanchi et al., 2004). However, there are some controversial studies
other accessory subunits (e, f, g, and A6L), are found associated with that do not support the substrate‐channeling role of SC. It has been
the c‐ring subunit. The F1 domain is present in the mitochondrial reported that quinone and quinol diffuse freely in and out of
matrix and contains soluble subunits: three α subunits, three β supercomplexes: substrate channeling does not occur and is not
subunits, and one of each of the γ, δ, and ε subunits (Dickson et al., required to support respiration (Fedor & Hirst, 2018; Hirst, 2018).
2006; Watt et al., 2010). α and β subunits constitute the catalytic
head of F1 and γ, δ, and ε subunits constitute the central branch that
acts as a bridge to connect the F1 head and c‐ring of F0 subunit 3 | RCS ALTERATIONS A ND
(Jonckheere et al., 2012; Pecina et al., 2018; Watt et al., 2010). MITOCHONDRIAL DISEASES
To summarize, ETC transfers electrons to mono‐oxygen and
generates H2O molecules associated with the pumping of protons A cell is exposed to various damaging genotoxic agents on a regular
from the matrix to the IMS through RCI, RCII, RCIII, and RCIV. The basis. Nuclear DNA has a robust damage repair system, which
proton electrochemical gradient thus created is utilized by F1 subunit enables it to rectify any deleterious alterations. However, mtDNA is
to force a conformational change in F0F1 ATP synthase and catalyze more susceptible to damage due to the lack of protective histones
the conversion of ADP to ATP (Jonckheere et al., 2012) (Figure 3a). and limited capacity for repairing (Ballard & Whitlock, 2004). In
addition, its proximity to ETC renders it prone to oxidative damage
and therefore shows a high degree of mtDNA mutation rate.
2.6 | Respiratory supercomplexes Moreover, the heteroplasmic mutations (coexistence of wild type
and mutant mtDNA) pose an additional challenge in diagnosing the
Interestingly, a growing body of structural evidence suggested that disease. For example, there may be both normal and defective
the different RC associates with each other to form supramolecular mitochondria with heteroplasmic mtDNA copies inside the cells at a
structures known as supercomplexes (SC) to perform their role more given time and the diseased phenotype would therefore be only
efficiently (Eubel et al., 2004; Schägger & Pfeiffer, 2000) (Figure 3b). apparent after the ratio between the two exceeds a threshold for
By genetically modulating the interactions between complexes I and biochemical deficiency (Stefano & Kream, 2016; Stewart & Chinnery,
III and III and IV, SC dynamism has been shown and it was also 2015). On the other hand, homoplasmic mtDNA mutations could also
demonstrated that they maintain electron transport using available evolve in the cells, as detected in human malignancies.
substrates (Lapuente‐Brun et al., 2013). For most complexes, crystal Mitochondrial respiratory chain disorders (MRCD) are
structures have been available (Rich, 2003). RCI has mainly been molecular–cellular and biochemical manifestations of mitochondrial
found to be associated with RCIII2 and RCIV (SCI + III2+ IV), also cytopathies and usually show progressive degenerative pattern.
Aberrant functioning of the OXPHOS system due to somatic or pathogenic mutations in LHON, Peverelli et al. observed five novel
inherited mutations in the mitochondrial proteins (nDNA and/or mutations in RCI. Two of those, 13340T>C and 13379A>G, were in
mtDNA encoded) is the main consequence of MRCD. There are MT‐ND5, while there was one mutation each in MT‐ND6 (14538A>G),
numbers of mtDNA mutations and depletions that have been MT‐ND3 (10350C>A), and MT‐ND1 (3632C>T) (Peverelli et al., 2021).
associated with MRCD (Vafai & Mootha, 2012). Although, the majority Some other type of rather rare mutations linked to LHON
of the mutations involve core structural components of RC, a significant are 1253T>C in MT‐ND4 (Liutkeviciene et al., 2021), 13345G>A in
number of anomalies have been reported for the proteins, associated MT‐ND5 (Engvall et al., 2021), 3890G>A in MT‐ND1 (Vacchiano et al.,
with the proper assembly of RC. One of the pivotal causes for this has 2021). Achilli et al. reported a case study in which they identified nine
been the large‐scale microchip screening for mutations in the nuclear rare mutations in MT‐ND1 (3700G>A,3733G>A‐C),4171C>A), MT‐
and mitochondrial genome (Brandon et al., 2005). ND4L(10663T> CA), and MT‐ND6 (14459G>A, 14495A>G,
14482C>A, and 14568C>T) (Achilli et al., 2012). Therapeutic
direction regarding LHON and RCI mutation have been reviewed in
3.1 | RCI alterations detail elsewhere (Sundaramurthy et al., 2021).
Apart from structural defects in core complex I components,
Defects in RCI are the most common cause of mitochondrial mutations in RCI assembly proteins can also lead to mitochondrial
disorders. The reason for this prevalence among other MRCD is dysfunction. For example, patients have been characterized with
often attributed to it being the largest enzyme of the OXPHOS deficiency in one of the RCI assembly protein, namely flavin adenine
machinery. The first instance of nuclear encoded RCI mutation in dinucleotide dependent oxidoreductase domain‐containing protein 1
NDUFS8, was reported in a patient with Leigh syndrome (LS) (Loeffen (FOXRED1) (Barbosa‐Gouveia et al., 2019). Defects in other assembly
et al., 1998). Since then, numerous RCI mutations were reported in proteins such as CIA30, C6ORF66 have also been reported resulting
various mitochondrial disorders (Bugiani et al., 2004; Kirby et al., in dysfunctional RCI (Dunning et al., 2007; Saada et al., 2008).
2004). These include mutations in either nuclear encoded genes such Altogether, dysfunction of RCI results in alteration of redox balance,
as NDUFGV1, NDUFS2, NDUFS4, or mtDNA encoded genes such as high ROS levels, and impaired calcium flux, all of which can have
MT‐ND1, MT‐ND2, MT‐ND3, MT‐ND4, MT‐ND4L, MT‐ND5, and MT‐ deleterious effects on the cell.
ND6. The most common mitochondrial disorders such as Mitochon-
drial encephalomyopathy, lactic acidosis, and stroke‐like episodes
(MELAS) syndrome, LS, and leber hereditary optic neuropathy 3.2 | RCII alterations
(LHON) have all been associated with the functional anomaly of RCI.
LHON is characterized by optic nerve atrophy, which leads to Mutations in nDNA encoded RCII proteins SDHs (SDHA, SDHB, and
sudden loss of vision. It has been suggested that the point mutation SDHC) lead to dysfunctional mitochondria, which can contribute to
observed in LHON leads to disruption of OXPHOS and elevated the development of LS, Carney–Stratakis syndrome, cardiomyopathy,
oxidative stress in the nerve endings of the cells, thereby causing late‐onset optic neuropathy, and paraganglioma. Defects in SDHA
neural atrophy. Early studies had pointed out that LHON occurs gene show autosomal dominant inheritance and case studies have
primarily as a consequence of RCI mutations. Several groups reported clinical manifestations such as bilateral optic atrophy and
demonstrated a correlation between MT‐ND6 mutations and LHON ocular movement disorder, and cardiomyopathy (Renkema et al.,
patients. The mutations identified in those studies were T14459A, 2015). A point mutation in SDHA gene, c.91C>T was reported in an
G14459A, T14484C, C14568T, T14596A, and C14482G (Howell LS patient (Renkema et al., 2015). In addition, mutation in SDHAF1
et al., 1998; Luberichs et al., 2002; Shoffner et al., 1995; Wissinger gene, an assembly factor, is also reported in RCII deficient patients,
et al., 1997). Chinnery et al. reported A14495G mutations in MTND6 causing symptoms such LS and leukoencephalopathy (Jain‐Ghai
in LHON patients, which led to general belief that ND6 is a et al., 2013).
mutational hotspot for LHON (Chinnery et al., 2001). Mimaki et al.
reported a couple of mutations in MT‐ND4 gene (G11778A and
G12192A) associated with LHON (Mimaki et al., 2003). Further, 3.3 | RCIII alterations
G11778A‐ND4 mutation also correlated with poor prognosis and
survival of LHON patients (Yu‐Wai‐Man et al., 2022). Carelli et al. Abnormalities of RCIII are less common compared to those of other
reported a correlation between LHON and a homoplasmic RCs. However, mutations in mtDNA encoded CYTB gene associated
m.11778G>A mutation in MT‐ND4. Interestingly, all those patients with alterations of RCIII functions have been reported (Acín‐Pérez
displayed a possible role of environmental factors in LHON as they all et al., 2004; Blakely, Mitchell, et al., 2005; Borek et al., 2016; Fisher &
had history of smoking and drinking (Carelli et al., 2016). Compre- Meunier, 2001). Mutations in Cytb such as G34S, G339E, and G290D
hensive analyses have now established a three‐gene alteration are also suspected to cause mitochondrial disease as their yeast
signature associated with the onset and pathogenesis of LHON counterparts have been implicated in RCIII deficiency (Fisher &
namely, m.3460G>A (MT‐ND1), m.11778G>A (MT‐ND4), and Meunier, 2001). Cytb mutation has also been observed in patients
m.14484T>C (MT‐ND6). In addition to various contributing with LHON. Weinberg et al. reported the importance of RCIII in the
maintenance of the suppressive function of Treg cells (S. E. Weinberg Dysfunctional complex III assembly has also been observed in
et al., 2019). RCIII defective mice inevitably show heightened and patients afflicted with lactic acidosis, hypoglycemia, hypotonia
lethal inflammatory immune responses (S. E. Weinberg et al., 2019). displaying a T59A mutation in UQCC3 (Ubiquinol‐cytochrome c
Carossa et al. reported a microdeletion in MT‐CYTB associated with reductase complex assembly factor 3) Gaignard et al. reported two
multisystem disease and exercise intolerance (Carossa et al., 2014). mutations, W96C and L215F, in CYC1, a nuclear gene encoding the
G14846A mutation in MT‐CYTB has been reported to be associated cytochrome c1 subunit of complex III in patients afflicted with
with Atherosclerosis (Volobueva et al., 2019). Further, a nonsense ketoacidosis and insulin‐responsive hyperglycemia. The authors
mutation (G15059A) in the MT‐CYTB gene correlated with exercise surmised that these mutations affected the tertiary structure of Cyt
intolerance and myoglobinuria (Andreu, Bruno, et al., 1999). Muta- c1, which makes it prone to proteolysis and thus inefficient assembly
tions in the MT‐CYTB namely G15084A, G15168A, and G15723A, of complex III (Gaignard et al., 2013).
one missense mutation (G14846A) and a 24‐bp deletion (from
nucleotide 15498 to 15521) were reported in a study of five patients
afflicted with exercise intolerance (mitochondrial myopathy). It was 3.4 | RCIV alterations
also established that mutation in MT‐CYTB were somatic and not
maternally inherited (Andreu, Hanna, et al., 1999). Hagen et al. RCIV alterations are unique as, in most cases the number of
reported two germline‐inherited mutations in Cytb, C93Y, and mutations in nuclear encoded subunits are more common than those
S246P, in patients afflicted by hypertrophic cardiomyopathy (HCM). of mtDNA encoded COX subunits (Brischigliaro & Zeviani, 2021;
Further, functional assessment of these mutations revealed that Sacconi et al., 2003). Most isolated COX deficiencies are inherited as
while C93Y mutation disrupts of the tertiary structure of Cytb, S246P autosomal recessive disorder and usually have early onset with poor
mutations affected macromolecular interaction of the Cytb (Hagen outcome. It is easier to assess the defects in COX in human tissues
et al., 2013). Mutations in the Cytb have also been linked to MELAS. and cells. However, tissue‐specific mutations of the RC may run the
In a study by Emmanuele et al., a heteroplasmic m.14864T>C risk of avoiding detection depending on the tissue samples being
mutation was observed in a patient suffering from MELAS. This analyzed. As with other RC alterations, mitochondria encoded
mutation resulted substitution of a cysteine residue with arginine MT‐CO1, MT‐CO2, and MT‐CO3 gene mutations can cause severe
within the Qn ubiquinone‐binding site and most likely affected the pathological conditions. On the other hand, single base pair deletion
proton translocation during ETC (Emmanuele et al., 2013). in MT‐CO2 leading to faulty assembly of the enzyme complex has
Mitochondrial disorders resulting from mutations in the nuclear been reported (Roos et al., 2019). Another form of complex IV
encoded components of RCIII have also been reported in the deficiency is known as isolated COX deficiency. This is caused due to
literature. Although, mitochondrial dysfunction resulting from muta- mutations in assembly factors and is one of the prevalent causes of
tions in nuclear encoded RCIII subunit such as UQCRB and RCIII mitochondrial disorders. One notable example of this condition is
Assembly protein BCS1L have been reported (Fernández‐Vizarra & mutation in COX6B1, which leads to destabilization of its expression
Zeviani, 2015). Furthermore, a rearrangement of QPC‐gene, also and adversely affects complex IV activity. Furthermore, this mutation,
called ubiquinol‐cytochrome c reductase (UQCRQ), which encodes for owing to its expression in lymphocytes, could serve as a better
subunit VII of RCIII has been linked to severe RCIII deficiency in the prognostic tool rather than in more invasive muscle biopsy (Abdulhag
livers of the affected individuals and show hepatomegaly and et al., 2015). Patients with Leigh's disease do not show any mutation
alterations in the levels of liver enzymes (Hemrika et al., 1994; De in COX genes. However, these patients possess mutations in surfeit
Lonlay et al., 2001). A recent study by Gusic et al. reported a gene (SURF1), which has an important role in COX biogenesis and
mutation in UQCRFS1, which encodes the Rieske iron‐sulfur protein mutation in SCO‐2 that is required for synthesizing cytochrome
and is crucial for the transfer of electron from Cytb to Cyt1 during oxidase. SCO‐1 and SCO‐2 are two crucial enzymes for the assembly
ETC (Gusic et al., 2020). This mutation caused mitochondrial of catalytic core of COX3. Mutations in these genes have been
cardiomyopathy, lactic acidosis, fetal bradycardia, and alopecia totalis. shown to cause copper deficiency and impaired complex IV activity
Furthermore, proper assembly of Rieske iron–sulfur protein requires (Hamvas et al., 1991; Leary et al., 2004).
a mitochondrial chaperone protein known as BCS1 homolog,
ubiquinol‐cytochrome c reductase complex chaperone (BCS1L).
(Nobrega et al., 1992). Mutations in gene encoding for this protein 3.5 | RCV alterations
has been primarily observed in patients with GRACILE syndrome
(Visapää et al., 2002). Another assembly factor associated with Defects in RCV pose a significant risk due to its role in ATP synthesis.
proper incorporation of Rieske Fe–S into complex III is LYRM7/ Mutations in either nuclear encoded ATP12 or mitochondria encoded
MZM1L (LYR motif containing 7) (Sánchez et al., 2013). A homozy- MT‐ATP6 and MT‐ATP8 can lead to dysregulation of complex V. In
gous mutation in gene encoding for this protein, c.73G>A transition addition, selective decrease in biosynthesis of the ATP synthase can
which causes replacement of aspartate residue with an asparagine at also result in the dysfunction of RCV. Methylglutaconic aciduria was
position 25, was observed in a patient suffering from early onset, one of the first disorders found to be associated with RCV alteration
severe encephalopathy and lactic acidosis (Invernizzi et al., 2013). (Holme et al., 1992). Besides, neuropathy, ataxia, and retinitis
F I G U R E 4 Mitochondrial disorders and respiratory complexes. Alterations in mtDNA and nDNA encoded respiratory complex molecules
giving rise to various mitochondrial disorders. CI‐V: Respiratory complex I‐V. mtDNA, mitochondrial DNA; nDNA, nuclear DNA.
pigmentosa (NARP) disorders have also been associated with mitochondria undergo several functional changes including increased
mitochondrial RCV alterations (Holt et al., 1990). NARP is caused production of ROS, imbalanced OXPHOS versus glycolysis that
by a point mutation in the mitochondrial genome at the nucleotide further favors tumorigenic progression (Chen et al., 2009; F.
position 8993 (T8993C or T8993G) affecting the MT‐ATP6 gene, Weinberg et al., 2010). In the 1920s, Otto Warburg identified the
which forms L156R or L156P mutant subunit of ATP synthase upregulation of aerobic glycolysis in cancer cells resulting in an
(Santorelli et al., 1993; Schon et al., 2001). This results in the loss of assumption that OXPHOS is downregulated in cancer cells. However,
assembly of ATP synthase, defective proton flow through F0, this is not the scenario in several cancers where upregulation of
elevated ROS levels and impaired OXPHOS (Baracca et al., 2000; OXPHOS has also been observed (Moreno‐Sánchez et al., 2007; S. E.
García et al., 2000; Nijtmans et al., 2001; Tatuch & Robinson, 1993). Weinberg & Chandel, 2015). Hence, it is important to understand the
It further affects the nervous system of the patients causing proximal pathophysiological effects of mitochondrial dysregulation in cancer
neurogenic muscle weakness, dementia, seizures, sensory neuropa- and unravel the underlying mechanisms critical for the development
thy, ataxia, cardiomyopathy, developmental delay and learning of the next generation of therapy and biomarkers.
problems and degeneration of the retina (Finsterer et al., 2018; Set
et al., 2019). Same mutation has also been associated with Leigh's
disease along with familial bilateral striatal necrosis encephalopathy 4.1 | Nuclear encoded RC genes’ alterations in
and cardiomyopathy (Jackson et al., 2017). Various mitochondrial cancer
diseases develop due to the alterations and perturbed function of
RCs are depicted in Figure 4. Different types of pathogenic mutations Alterations in nuclear encoded RC genes have been reported in
in nuclear and mitochondria encoded RC genes associated with different types of cancer. SDH mutations have been associated with
mitochondrial disorders have been presented in Table 1. a variety of cancers including prostate, paraganglioma, and pheo-
chromocytoma (Belinsky et al., 2017; Casey et al., 2017; Huang et al.,
2020; Rednam et al., 2017). A most recent and comprehensive study
4 | F UN C T I O NA L T UR M O I L OF RC S A ND by Gault et al. reported a number of mutations such as c.91C>T,
CANCER c.1141C>G, and c.1A>G (Gault et al., 2018). In their study, they
conclude that c.91C>T (p. Arg31Ter) mutation in the SDHA gene has
Cancer cells have a unique property to reprogram and adapt to the an important role in neuroblastoma and gastrointestinal stromal
cellular functions necessary for sustained growth and progression tumor (GIST), although its role in other types of cancers is not
(Khan et al., 2020; Wang et al., 2018). In this journey, cancer cells' definitive. Another study reported a novel c.1A > C mutation in the
TABLE 1 List of pathogenic mutations in nuclear and mitochondrial encoded respiratory complexes
Gene Mutation Disease References

NDUFA1 c.32R>G Retinitis pigmentosa Fernandez‐Moreira
et al. (2007);
c.22G>C LS/LS‐like
Morán et al. (2010);
c.55C>T LS Potluri et al. (2009);
Uehara et al. (2014)
c.94G>C Lactic acidosis/leukodystrophy
c.111G>C Progressive neurodegeneration
c.251G>C Encephalomyopathy
NDUFA2 c.208G>A LS Hoefs et al. (2008)
c.221G>A
NDUFA8 325G>A LS Bugiani et al. (2004)
NDUFA9 c.962G>C LS van den Bosch et al. (2012)
NDUFA10 c.1A>G + c.425A>G LS Haack et al. (2012)
c.296G>A Muscular hypotonia
NDUFA11 IVS1 + 5G>A Lethal infantile mitochondrial disease/ Berger et al. (2008)
encephalocardiomyopathy
NDUFA12 c.178C>T LS Ostergaard et al. (2011)
NDUFA13 c.107T>C LS González‐Quintana

et al. (2020)
c.194delT LS
NDUFB9 c.191T>C Muscular hypotonia Haack et al. (2012)
NDUFS1 c.212T>A + c.384T>A Muscular hypotonia Bugiani et al. (2004);

Ferreira et al. (2011);
c.497G>A + c.683T>C Leukodystrophy
Iuso et al. (2006);
c.664‐666del + c.755A>G Leukoencephalopathy Pagniez‐Mammeri
et al. (2010)
c.683T>C + c.755A>G Leukoencephalopathy/leukodystrophy
c.691C>G LS
c.721C>T Unspecified encephalomyopathy
c.1222C>T LS/leukoencephalopathy
c.1564C>A Leukoencephalopathy/encephalopathy
c.1669C>T + c.1783A>G Leukodystrophy
c.1699C>T + c.631‐ Leukoencephalopathy

633delGAA
c.1783A>G Progressive cavitating Leukoencephalopathy
c.1855G>A Leukoencephalopathy
c.1912INS.A + c.2084A>G Leukodystrophy
c.2083T>C + c.2084A>G Leukodystrophy
c.2119A>G LS‐like
NDUFS2 c.58C>A Encephalomyopathy Bugiani et al. (2004);

Ngu et al. (2012);
c.329A>T + c.968G>A Lactic acidosis
Tuppen et al. (2010)
c.413G>A + c.998G>A LS‐like
c.671C>T Severe neonatal hypotonia, dysmorphic

features and epilepsy
c.683G>A Hypertrophic cardiomyopathy and

encephalomyopathy
(Continues)
TABLE 1 (Continued)

c.686C>A Hypertrophic cardiomyopathy and
encephalomyopathy
c.875T>C + c.353G>A LS
c.875T>C + c.442G>A LS
c.875T>C + c.866 + 4A>G LS‐like
c.875T>C + c.1328T>A LS
c.1054G>C Encephalomyopathy
c.1237T>C Encephalomyopathy
c.1336G>A LS
NDUFS3 c.434C>T + c.595C>T LS Bénit et al. (2004)
c.668C>T Unspecified encephalomyopathy
NDUFS4 c.9‐1G>A9 LS‐like Budde et al. (2003);

Iuso et al. (2006);
c.44G>A Encephalopathy/LS‐like
Petruzzella et al. (2003)
c.289‐290delG LS
c.316C>T LS
c.351‐2A>G + c.99‐1G>A LS
c.355G>C + c.462delA LS‐like
c.392T>C + c.462delA + LS
c.99‐1G>A
(+NDUFS2:c.96‐3C>T)
c.462delA LS‐like
c.462delA + c.99‐1G>A LS
c.466–470Ins.AAGTC Unspecified encephalomyopathy
NDUFS6 c.186 + 2T>A Lethal infantile mitochondrial disease Kirby, McFarland,

et al. (2004)
4.175‐kb exons 3 and 4 Lethal infantile mitochondrial disease
c.344G>A Neonatal lactic academia
c.352C>T Muscular hypotonia
NDUFS7 c.17‐1167C>G LS Triepels et al. (1999)
c.364G>A LS
c.434G>A LS
NDUFS8 c.52C>T Encephalomyopathy Procaccio and

Wallace (2004)
c.236C>T LS‐like
c.236C>T + 305G>A LS
c.254C>T + c.413G>A LS
c.460G>A (+c.826G>A) Leukoencephalopathy
NDUFV1 c.175C>T + 1268C>T Progressive unspecified encephalomyopathy Calvo et al. (2010)
c.611A>G + c.616T>G LS‐like/LS
c.632C>T Hypotonia and lactic acidosis
c.640G>A LS
c.770G >A + 632T>C Leukoencephalopathy

TABLE 1 (Continued)

c.1022C>T Leukoencephalopathy/leukodystrophy and
myoclonic epilepsy
c.1129G>A Lethal infantile mitochondrial disease

(+C20orf7:c.412G>A)
c.1158C>G Leukoencephalopathy
c.1294G>C + c.989‐990del‐2 LS
NDUFV2 c.86C>T Encephalomyopathy Laugel et al. (2007;

M. Schuelke et al. (1999)
IVS2 + 5 + 8delGTTA Hypertrophic cardiomyopathy and
Encephalopathy
SDHA c.64‐2A>G Leigh syndrome Alston et al. (2012);

Korpershoek
c.91C>T Paraganglioma
et al. (2011);
c.1065‐3C>A Ma et al. (2014);
Renkema et al. (2015)
c.565T>G
c.G117G/del Mitochondrial encephalopathy
c.T220T/insT Leukodystrophy
c.1523C>T
c.1526C>T
SDHB c.143A>T Leukodystrophy Alston et al. (2012)
MT‐ND1 3308T>C BSN, MELAS, sudden infant death syndrome Abu‐Amero and
Bosley (2006);
3481G>A MELAS
Blakely, de Silva,
3308T>G MELAS/LHON et al. (2005);
Malfatti et al. (2007);
3376G>A LHON
McFarland, et al. (2004);
3460G>A LHON Mitchell et al. (2006);
Munakata et al. (2004);
3644T>C Bipolar disorder, MELAS Opdal et al. (2002);
3697G>A LS Rocha et al. (1999)
3733G>A LHON
3796A>G Adult‐onset dystonia
3946G>A MELAS
3949T>C MELAS
4171C>A LHON
MT‐ND2 4681T>C LS Brown et al. (1995);

Ugalde et al. (2007)
5244G>A LHON
MT‐ND3 10158T>C LS McFarland et al. (2004);

Sarzi et al. (2007);
10191T>C ESOC/Leigh‐like
Wilfert et al. (2017)
10197G>A Leigh, dystonia
MT‐ND4L 10663T>C LHON Abu‐Amero

and Bosley (2006)
MT‐ND4 11232T>C Chronic progressive external ophthalmoplegia Deschauer et al. (2003);

X. Zhou et al. (2006)
11696G>A LHON
11777C>A LS
11778G>A LHON
(Continues)
TABLE 1 (Continued)

11832G>A Exercise intolerance
11994C>T Low sperm motility
MT‐ND5 12706T>G LS Engvall et al. (2021);

Mayorov et al. (2005);
12770A>G MELAS
Ruiter et al. (2007);
12782T>G LHON Wilfert et al. (2017)
12848C>T LHON
13042G>A LHON‐like
13045A>C MELAS/LHON/LS
13063G > A Leigh
13084A>T LHON
13345G>A MELAS/LS
13513G>A MELAS/LS
13514A>G MELAS
MT‐ND6 14453G>A MELAS Kishita et al. (2021);

Malfatti et al. (2007);
14459G>A LHON and dystonis/LS
Uehara et al. (2014)
14482C>A LHON
14482C>G LHON
14484T>C LHON
14487T>C Dystonia/LS
14495A>G LHON
14498T>C LHON
14596A>T LHON
14600G>A Ataxia
14439G>A LS
14597A>G LS
MT‐CYB 14787delTTAA PD/MELAS Andreu, Bruno, et al. (1999);

Andreu, Hanna, et al.
(1999);
14849T>C Septo‐optic dysplasia, Brown et al. (1995);
De Coo et al. (1999);
14864T>C exercise intolerance,
Keightley et al. (2000);
14841A>G rhabdomyolysis, HCM, RP Legros et al. (2001);
Mancuso et al. (2003);
15059G>A Mitochondrial myopathy (MM)
Markus Schuelke et al.
15084G>A Exercise intolerance (2002);
Yang et al. (2009);
15150G>A Exercise intolerance Yiş et al. (2015)
15197T>C Exercise intolerance
15242G>A Mitochondrial encephalomyopathy
15243G>A Hypertrophic cardiomyopathy
15257G>A LHON
15497G>A Paracrystalline inclusions with exercise

intolerance
TABLE 1 (Continued)

15498del24 Exercise intolerance
15498G>A Hypertrophic cardiomyopathy
15579A>G Multisystem disorder, exercise intolerance
15615G>A Exercise intolerance; antimycin resistance
15699G>C SNHL, migraine, muscle weakness
15761G>A MM
5920G>A Myoglobinuria, exercise intolerance
MT‐CO1 6020del5 Motor neuron disease Bruno et al. (1999);

Clark et al. (1999);
6489C>A Seizures
Comi et al. (1998);
6708G>A MM and rhabdomyolysis Gattermann et al. (1997);
Karadimas et al. (2000);
6721T>C Acquired idiopathic sideroblastic Anemia
Kollberg et al. (2005)
6742T>C Acquired idiopathic sideroblastic Anemia
6930G>A Multisystem disorder
7443A>G Deaf
7444G>A LHON, SNHL, deaf
7445A>C Deaf
7445A>G SNHL
7587T>C Mitochondrial encephalomyopathy
MT‐CO2 7671T>A MM Campos et al. (2001);

Clark et al. (1999);
7706G>A Alpers–Hutternlocher‐like
Horváth et al. (2005);
7896G>A multisystem disorder Rahman et al. (1999);
Uusimaa et al. (2003)
7970G>T Encephalopathy, multisystem disorder
7989T>C Rhabdomyolysis, exercise intolerance
8042del2 Severe lactic acidosis, liver failure, neonatal

death
9379G>A Progressive myopathy, exercise intolerance,

lactic acidosis
MT‐CO3 9438G>A LHON secondary myoglobinuria Abu‐Amero et al. (2005);

Hanna et al. (1998);
9487del15
Johns et al. (1994);
9537insC Leigh‐like Matsumoto et al. (1999);
Tiranti et al. (2000)
9738G>T LHON
9789T>C Myopathy, rhabdomyolysis, exercise intolerance
9952G>A Encephalopathy, exercise intolerance
9957T>C PEM, MELAS, nonarteritic ischemic optic

neuropathy (NAION)
MT‐ATP6 8851T>C Neurological disorder Abu‐Amero et al. (2005);

Carrozzo et al. (2000);
8993T>C NARP/LS
De Meirleir et al. (1995);
8993T>G NARP/LS Dionisi‐Vici et al. (1998);
Makino et al. (1998);
(Continues)
TABLE 1 (Continued)

9176T>C BSN/LS Moslemi et al. (2005);
Temperley et al. (2003)
9176T>G LS
9185T>C LS
9191T>C LS
9205delTA Seizures, lactic acidemia
SDHA in GIST (Carrera et al., 2019). These studies show a strong of RCI subunits NDUFA13 and NDUFS3 (nDNA encoded) was found
correlation between SDHA mutation and GIST in addition to to be associated with EMT changes (Li & Li, 2015). Reduced levels of
paraganglioma and pheochromocytoma. Saxena et al. observed an RCI subunits including NDUFA13, NDUFS3, and accessory subunit
R46Q mutation in SDHB in renal cell carcinoma. This mutation NDUFB9 have been correlated with increased invasiveness in BC
impairs the Fe–S clusters acquisition, renders SDHB unstable, and cells (X. He et al., 2013; L. D. Li et al., 2015; Putignani et al., 2012). On
hindered the assembly of SDHB in complex II (Saxena et al., 2016). the other hand, reduced expression of NDUFB9 has been observed in
The functional consequence of mutations depends on the subunit highly metastatic BC cells (L. D. Li et al., 2015). Furthermore, its
being affected. For example, mutations in the SDHB, C and D knockdown produces high levels of mitochondrial ROS, a decrease of
subunits would also result in enhanced ROS production as these NAD+/NADH ratio mediated by Akt/mTOR/p70S6K signaling path-
subunits are involved in subsequent transfer of electrons to Cytb and way along with enhanced expression of mesenchymal markers
mutation in these would lead to leakage of electrons. On the other resulting in promoting EMT (L. D. Li et al., 2015).
hand, since SDHA is the primary electron acceptor of complex II, On the other hand, elevated rate of glycolysis and TCA cycle flux
mutations would block the entry of electrons altogether, which were found to be associated with activation of oncogenic drivers,
would abolish the production of ROS. including MYC and KRAS, and also affect PI3K pathway in cancer cells
Metabolic rewiring appears to be an integral part of metastatic (S. E. Weinberg & Chandel, 2015). Increased glycolytic rate generates
adaptation, where cancer cells wisely use mitochondria for their metabolic intermediates that gets involved in several biosynthetic
survival benefits. In a systemic analysis of 20 different cancers, pathways essential for cell proliferation, including the pentose
disruption of OXPHOS activity was shown to be associated with an phosphate pathway (PPP) that produces ribose and cytosolic NADPH
induction of epithelial‐to‐mesenchymal transition (EMT) phenotype and one‐carbon metabolism for the production of mitochondrial
and poor clinical outcome (Gaude & Frezza, 2016). Reduced NADPH, nucleotide synthesis, and methylation reactions (Vander
expression of various TCA cycle enzymes and the mitochondrial Heiden & DeBerardinis, 2017). During tumorigenic progression, many
SDH D (SDHD) was also evident in this analysis. In lung fetal and metabolic changes are accumulated in cancer cells. Of particular
cancer cell lines, high glycolysis to low OXPHOS activity accompa- relevance is the upregulation of Hexokinase II in several tumors
nied with lower mitochondrial biogenesis and PGC1 alpha expression (Mathupala et al., 2010). It plays an important role in the production
was reported (Bellance et al., 2009). Interestingly, an earlier study of molecules required for the proliferation of cancer cells. Removal of
demonstrated the promotion of KRAS‐driven tumorigenicity through hexokinase from the mitochondrial membrane of cancer cells induces
altered mitochondrial metabolism and ROS production (Weinberg apoptosis (Azoulay‐Zohar et al., 2004; Chiara et al., 2008). In colon
et al., 2010). A correlation has been observed in the mitochondrial cancer cells, it has been reported to be an interesting target to
dysfunctions and content of OXPHOS complexes in renal cancers of activate cell death. In this study, enhanced apoptosis and growth
hereditary origin (Simonnet et al., 2002). In renal cell carcinoma, inhibition has been observed by stable RNA interference of
decrease OXPHOS was correlated with the fast growth and hexokinase II gene (Peng et al., 2008). Studies in pancreatic cancer
aggressiveness of tumors (Simonnet et al., 2002). Studies from other have suggested that cancer stem cells involved in metastasis and
laboratories also reported downregulation of some RCI subunits in tumorigenesis depend more on OXPHOS (Viale et al., 2014, 2015).
mouse and human cell lines and their association with increased ETC proteins have been found to be upregulated in BC cells
invasion and migration (Ishikawa et al., 2008; L. D. Li et al., 2015; compared to normal epithelial cells by histochemical staining of
Y. Yuan et al., 2015). In human BC cell lines, knockdown of the nDNA functional mitochondria. In this method, RCI, II, and IV activity has
encoded RCI subunit NDUFV1 was found to be associated with been assayed by NADH, SDH, and cytochrome oxidase, respectively
+
decreased NAD /NADH ratio accompanied with enhanced Akt and (Whitaker‐Menezes et al., 2011). RNA and protein analysis revealed
mTORC1 activities and reduced levels of autophagy (Santidrian et al., that OXPHOS upregulation in BC cells with retinoblastoma tumor‐
2013). These alterations were associated with enhanced metastatic suppressor gene (RB1) deficiency results in increasing stemness and
potential of the BC cells. Besides, in HeLa cells, decreased expression metastasis (Jones et al., 2016; Zacksenhaus et al., 2017). An increase
in the expression of OXPHOS genes, mitochondrial mass, ETC encoded subunits (Iommarini et al., 2018). This was demonstrated by
protein expression, oxygen consumption rate (OCR), and decrease in Lim et al. in their study on human 143B cybrid cells carrying a
lactate production mediated by NF‐κβ has been observed in classical homoplasmic MT‐ND1 mutation. Lack of ND1 resulted in not only
Hodgkin lymphoma (Birkenmeier et al., 2016). From mitochondrial halting of complex I assembly but also the formation of super-
protein and gene expression analysis, it has also been reported that complexes (Lim et al., 2016).
ETC components are upregulated in the OXPHOS‐high subset RCI The authors have also identified a heteroplasmic mtDNA
and RCIV in particular (Caro et al., 2012). Depending on BCL‐2 mutation in MT‐ND1 and MT‐CYTB (RCIII) in these cells. On the
oncogene expression, OXPHOS is also found to be high in acute other hand, in mouse‐derived Lewis lung carcinoma cells, ND6
myelogenous leukemia (AML) cells (Lagadinou et al., 2013). In mutation was found to be associated with altered RCI activity,
pancreatic ductal adenocarcinoma (PDAC), a strong dependence of increased ROS generation, and enhanced metastasis (Ishikawa et al.,
pancreatic stem cells on augmented OXPHOS and decreased 2008). For progressive growth, cancer cells often facilitate clonal
glycolysis has been observed using RNA and metabolic analyses expansion of driver mutations. In nonsmall cell lung cancer and head
(Viale et al., 2014). These stem cells are found to be drug‐resistant and neck squamous cell carcinomas, clonal expression of coding
(Lonardo et al., 2013). Upregulated OXPHOS has also been reported mtDNA mutation from RCI, RCIII, RCIV, and RCV were noted in
in myeloid leukemia stem cells using metabolomics and functional progressive cancer tissues or histologically normal appearing tissues
analyses (Kuntz et al., 2017). A recent study demonstrating increased (Schubert et al., 2020). Interestingly, certain RCs appear to the
oxidative metabolism of pancreatic cancer cells under severe hypoxia hotspots for mtDNA mutations. In breast carcinomas, RCV and RCI
through stabilized mitochondrial SC activity further support this appeared to be the most frequently affected region of the mtDNA
notion (Hollinshead et al., 2020). Remarkably, blocking of the SC (Alhomidi et al., 2013; Grzybowska‐Szatkowska et al., 2014; Yadav &
formation inhibited hypoxic pancreatic cancer cell growth. Thus, Chandra, 2013), while in prostate and urothelial carcinomas,
metabolic reprogramming through functional alterations of nDNA predominant mtDNA mutations were detected RCIV, RCI, and RCIII
encoded RC molecules contributes to malignant progression. Nota- regions (Dasgupta, Shao, et al., 2012; Duberow et al., 2016; Hopkins
bly, majority of these studies described above were conducted in et al., 2017; Petros et al., 2005; Schöpf et al., 2020). A recent study
cultured murine and human cells line and subcutaneous models. A explored the mitochondrial genome in 268 early‐stage PDAC and
comprehensive and careful analysis of OXPHOS expression and identified that RCI harbors the majority of the coding mtDNA
activity in human tumors of different anatomic origins remains to be mutations (Hopkins et al., 2018). Moreover, the RCI mutation in MT‐
determined. A list of mutations concerning the nuclear encoded ND4 and MT‐ND6 were found to be associated with shorter survival.
mitochondrial RC genes is mentioned in Table 1. Notably, some studies also demonstrated that patient derived RC‐
specific mtDNA mutations promote high ROS production, OXPHOS
function, growth and progression of urothelial, lung, prostate and
4.2 | RC alterations involving mitochondrial head and neck cancer reflecting cancer promoting role of RC‐specific
genome in cancer mtDNA mutations (Dasgupta et al., 2008; Dasgupta, Hoque, et al.,
2009; Dasgupta, Soudry, et al., 2012; Petros et al., 2005; W. Sun
Coding mtDNA alterations impacting various RCs’ function also et al., 2009; Zhou et al., 2007). In an in vivo cybrid model of 143B
appeared to be pronounced in human malignancies. Of note, cancer osteosarcoma, transplantation of MT‐ND4 and MT‐ND6 mutant cells
cells without mtDNA do not appear to exhibit enhanced tumorigenic (RCI mutations) results in higher tumor growth, which was associated
potential but after acquiring healthy mtDNA, they regain their with small decrease in OXPHOS function (Cruz‐Bermúdez et al.,
tumorigenic potential and promote progression, implicating the 2015). In addition to mtDNA sequence variants, increase in mtDNA
dependency of the cancer cells on mtDNA in acquiring metastatic content have also been regarded as a mark of increased OXPHOS
capabilities (Bajzikova et al., 2019; Tan et al., 2015). The extent and function and demonstrated in several cancers including acute
nature of coding mtDNA mutations and their impact on RC lymphoblastic leukemia, non‐Hodgkin lymphoma, endometrial cancer,
expression and activity have been explored in human malignancies. colorectal cancer, ovarian cancer, prostate cancer, head and neck
In a study on thyroid carcinoma, cybrid models were generated using cancer, lung adenocarcinoma, esophageal squamous cell carcinoma,
human thyroid carcinoma cell line XTC.UC1 and nononcocytic cell and thyroid cancer (Dasgupta, Soudry, et al., 2012; Dasgupta,
lines TPC‐1 (Bonora et al., 2006). While measuring the growth of the Yung, et al., 2009; Reznik et al., 2016; Yu, 2011).
cells in glucose versus galactose medium, the thyroid carcinoma cell
line XTC.UC1 failed to produce sufficient ATP and survive well in
galactose medium during long culture. Further investigation revealed 5 | TEC HN I QUES FOR I DENT IFYING
loss of expression of mtDNA encoded ND1 and ND6 and nDNA M T D N A A L T E R A TI O N S
encoded RCI proteins NDUFA9, NDUFS3 and in these cells.
Decrease in expression of the nuclear encoded RCI components Southern blot is the oldest method for the detection of mtDNA
can be explained by a halt in the assembly of complex I, which is a rearrangements. This method basically involves the use of isolation of
stepwise process, due to lack of sufficient amount of mitochondrial mtDNA from nondividing cells and subjecting it to digestion by
TABLE 2 List of ongoing and completed clinical trials in mitochondrial diseases
|4064
Therapeutic strategy/
Disorders mechanism Gene/target/drugs Clinical trial status Outcome Reference
Mitchondrial cytopathies, mutation in Antioxidant therapy Coenzyme Q10 (CoQ10 Phase III (completed) No statistical significant difference between NCT00432744
mtDNA, or nuclear DNA CoQ10 versus Placebo
MELAS Antioxidant Idebenone Phase IIa, randomized No statistical significant difference between NCT00887562)
Mitochondrial Encephalopathy Lactic (completed) idebenone versus Placebo
acidosis
LHON Antioxidant Idebenone Open‐label intervention Ongoing NCT02774005)

study NCT02771379)
LHON Antioxidant Idebenone A double‐blind, randomized, No statistically significant difference in (NCT00747487)

placebo‐controlled primary outcome different between
study idebenone and the placebo group
Inherited mitochondrial disease, Antioxidant Cysteamine bitartrate Phase II Terminated due to lack of efficacy NCT02023866
including leigh syndrome NCT02473445
Pearson syndrome Redox modulator EPI‐743 Phase II Terminated NCT02104336
LS Redox modulator EPI‐743 Phase II Completed NCT01721733
Primary mitochondrial myopathy Antioxidant Elamipretide Phase III Terminated (did not meet the primary end NCT03323749
points)
LS Redox modulator EPI‐743 Phase II Active NCT02352896
LHON Antioxidant Elamipretide Phase II Completed NCT02693119
MELAS, MIDD LHON Antioxidant KH176 Phase II Completed NCT02909400
MM Mitochondrial biogenesis Bezafibrate Phase II Completed (reduction in complex IV‐deficient NCT02398201

augmentation muscle fibers and improvement in cardiac
function).
Mitochondrial myopathies, fatty acid Mitochondrial biogenesis Resveratrol Double‐blind, randomized Completed NCT03728777
oxidation defects augmentation trial
Mitochondrial myopathies Mitochondrial biogenesis RTA 408 Phase II Completed; (no differences in peak cycling NCT02255422
augmentation exercise workload. Reduced heart rate and
lactate levels during submaximal exercise
Mitochondrial diseases Mitochondrial Mitochondrial biogenesis Nicotinamide Riboside Interventional (Clinical Trial) Active NCT03432871
myopathies, LHON augmentation
Mitochondrial myopathies Mitochondrial biogenesis Niacin Interventional (Clinical Trial) Completed NCT03973203
augmentation
Mitochondrial respiratory chain Mitochondrial biogenesis KL1333 Phase I Active NCT03888716

deficiencies, MELAS syndrome augmentation
VIKRAMDEO
ET AL.
restriction enzymes followed by agarose gel electrophoresis (Moraes
NCT03406104,
NCT03153293
et al., 1989; Tang et al., 2000). Anomalous band on the gel reveals the
NCT03293524,
NCT03747328
NCT03952234
NCT04475549
NCT03866954
NCT02427178
NCT02064569
Reference presence of rearrangement of mtDNA. Usually, around four restric-
tion enzymes that differ in their restriction sites in the mitochondrial
genome are used for this technique which allow for a more robust
characterization. The limitation of this technique is the lack of
reliability when the cells’ population harboring a mutant phenotype
and rearranged mtDNA is too small.
PCR analysis bypasses the limitation of southern blot technique.
PCR can specifically amplify partially deleted mtDNA from cell with
both wild‐type and mutant phenotypes, separate electrophoretically
and compare the differences between them. This technique is limited
only by the number of primers that can be tested considering the
variable nature of the deletion in mtDNA. However, amplification of
Not yet recruiting
Not yet recruiting
D‐loop region of mtDNA has immensely eased the detection of

deleted mtDNA sequences (Ballantine & Boxer, 1986; R. T. Yuan et al.,
Completed
recruiting
Outcome
2015; Y. B. Zhao et al., 2005). In contrast to the detection of mtDNA

Active
Active
Active
rearrangement, identifying the point mutations in the mtDNA

requires mtDNA from dividing cells. A variety of different techniques
such as PCR restriction fragment length polymorphism, denaturing
gradient gel electrophoresis or single‐strand conformation polymor-
Clinical trial status
phism and next‐generation sequencing (NGS) are now being used to

identify mutations in the mtDNA of patients (Ahn et al., 2015; Alonso
et al., 1997; IHe et al., 2003; Marquis et al., 2017; Yoon et al., 1991).
Phase III
Phase II
Phase II
Phase II
Phase II
Phase II
Phase I
NGS has been especially useful in characterizing heteroplasmy in

patients and when coupled with high throughput microarrays,
provides a comprehensive and precise approach for the assessment
Erythrocyte encapsulated
Allogeneic hematopoietic
of mitochondrial mutations (Maitra et al., 2004; Yao et al., 2019). For

GS010 (rAAV2/2‐ND4)
stem cell transplant
the same reason, NGS techniques are most widely used method for
Gene/target/drugs
phosphorylase
the assessment of mitochondrial mutations. A very recent study

thymidine
combined the specificity of CRISPR (clustered regularly interspaced

L‐Citrulline
short palindromic repeats) system and the robustness of isothermal

IW‐6463
ABI‐009
GS010
techniques such as transcription‐mediated amplification (TMA) and

provides a potentially cheaper and faster method to detect
mitochondrial mutations (Jiang et al., 2021).
Enzyme replacement therapy
Restoration of nitric oxide
Restoration of nitric oxide

Modulation of mitophagy
Therapeutic strategy/
Stem cell transplant
6 | D E V E L O P M E N T OF M I T O C H O N D R I A L
D I S E A S E MA N A G E M E N T ST R A T E G I E S
Gene therapy
Gene therapy
mechanism
The most influential factors in mitochondrial pathology are heritabil-

ity, age, sex, and lifestyle patterns, the last of which is often an
important factor in civilization diseases such as obesity, diabetes, and
Mitochondrial neurogastrointestinal
heart diseases. First step toward characterizing these factors is

assembly of large and meticulously phenotyped patients’ cohorts so
Leigh or Leigh‐like syndrome
that their role in genetic linkage could be elucidated. Furthermore,

(Continued)
this information could help to decipher the potential of nuclear

encephalomyopathy
events to drive the phenotype in mitochondrial disease. Age is an

MELAS syndrome
important factor associated with mitochondrial abnormalities. One of

the widely accepted reasons for this is the gradual accumulation
TABLE 2
Disorders
(MNGIE)
of ROS with age which can help in both induction and propagation of
MNGIE
MELAS
LHON
LHON
mutations in the mitochondrial genome. This link is corroborated by

the Newcastle Mitochondrial Diseases Adult scale, which shows the
F I G U R E 5 Development of mitochondrial disorders and their management strategies. Factors influencing the onset and progression of
respiratory complex associated mitochondrial disorders and malignant transformation. Multimodal high‐throughput approaches can be
employed to improve current disease management strategies.
correlation between increases in mitochondrial mutations with age. In alter RC complex assembly and activity in a patient‐specific manner,
addition, biological sex is also linked to the mitochondrial disorder, an would be very useful to develop novel therapeutic tools (Ashton
example being LHON, which afflicts males more than females. A et al., 2018; Ghosh et al., 2020). To this end, the next‐generation
possible reason for this has been attributed to the cytoprotective deep sequencing approach remarkably improved the detection of
effect of estrogen. Apart from this, consumption of alcohol, smoking, heteroplasmic as well as homoplasmic mtDNA/nDNA mutations,
carbon monoxide poisoning, and antiretroviral therapy are also which can even be performed in a single cell level. Such approaches
known to cause mitochondrial disorders. Recent studies led to the have been very fruitful in better cancer diagnosis, monitoring, and
identification of fibroblast growth factor 21 (FGF‐21) as a promising developing effective treatment of various cancers including breast,
serum biomarker for mitochondrial disease (Morovat et al., 2017). lung, head and neck, pancreas, and melanoma by targeting growth
With its high specificity and sensitivity, FGF‐21 is a promising regulatory molecules Estrogen receptor (ER), Progesterone receptor
diagnostic tool for muscle‐affecting mitochondrial respiratory dis- (PR), Human epidermal growth factor receptor 2 (HER2), Epidermal
orders, which might be a useful first‐line diagnostic tool instead of growth factor receptor (EGFR), KRAS, Liver kinase B1 (LKB1), and
the invasive muscle biopsy currently performed in clinical settings. In BRAF. To summarize, utilizing the cutting‐edge technologies,
recent research endeavors, many studies are ongoing such as comprehensive profiling of RC alterations at various levels as
OXPHOS targeted therapy (Ghosh et al., 2020; Sica et al., 2020), depicted in Figure 5, could be useful in developing suitable
mtDNA replacement therapy (Wolf et al., 2015), transplantation of therapeutics for better management of mt‐associated diseases
normal healthy mt (Lightowlers et al., 2020) to cure various including cancers.
mitochondrial diseases. Some of the current approaches that are
being considered for the treatment of mitochondrial disorders are
antioxidant‐based therapies, stem cell‐based therapy, gene therapy, 7 | C O N C L U S I O N A ND FU TU R E
and augmentation of mitochondrial biogenesis. Current and ongoing PERS P ECTI V E
trials utilizing these strategies are summarized in Table 2.
Considering the emerging role of mitochondrial RC alterations in A growing body of evidence, as discussed above, supports that
human malignancies, cataloging and functional characterization of the defects in RC assembly and functions play a significant role in the
mtDNA and nDNA encoded mitochondrial gene mutations, which development of various OXPHOS‐associated mitochondrial diseases
and cancer. Imbalance in mtDNA integrity, subsequent evolution, European Journal of Human Genetics, 23, 159–164. https://doi.org/
selection, and maintenance of heteroplasmy or a state of homo- 10.1038/ejhg.2014.85
Abu‐Amero, K. K., & Bosley, T. M. (2006). Mitochondrial abnormalities
plasmy with mutant mtDNA (RC specific) appear to be critical in
in patients with LHON‐like optic neuropathies. Investigative
determining cellular fate and survival. Thorough understanding of the Ophthalmology and Visual Science, 47(10), 4211–4220. https://doi.
molecular programs that allow the cells to adapt to these states, org/10.1167/iovs.06-0295
could be useful to advance our knowledge in mitochondrial biology. Abu‐Amero, K. K., Bosley, T. M., Bohlega, S., & Hansen, E. (2005).
The functional imbalance in the RCs is largely attributable to genetic Mitochondrial T9957C mutation in association with NAION and
seizures but not MELAS. Ophthalmic Genetics, 26, 31–36. https://
alterations in mtDNA or nDNA encoded molecules being transported
doi.org/10.1080/13816810590918235
to the mitochondria. Notably, despite having a small genome, the
Achilli, A., Iommarini, L., Olivieri, A., Pala, M., Hooshiar Kashani, B.,
mitochondria encoded RC subunits' alterations appear to be powerful Reynier, P., La Morgia, C., Valentino, M. L., Liguori, R., Pizza, F.,
in driving the development of mitochondrial disorders or promoting Barboni, P., Sadun, F., de Negri, A. M., Zeviani, M., Dollfus, H.,
tumorigenesis. To this end, ROS, generated through the imbalanced Moulignier, A., Ducos, G., Orssaud, C., Bonneau, D., … Carelli, V.
(2012). Rare primary mitochondrial DNA mutations and probable
RC activity can act as oncogenic stimulants in supporting onco-
synergistic variants in Leber's hereditary optic neuropathy. PLoS
genesis. Consequently, the anomaly in RC assembly and activity, One, 7, 42242. https://doi.org/10.1371/journal.pone.0042242
including “supercomplex” formation, further supports the growth and Acín‐Pérez, R., Bayona‐Bafaluy, M. P., Fernández‐Silva, P., Moreno‐
survival of tumor cells in adverse conditions such as starvation, Loshuertos, R., Pérez‐Martos, A., Bruno, C., Moraes, C. T., &
Enríquez, J. A. (2004). Respiratory complex III is required to maintain
chemotherapeutic, and targeted treatments. Hence, it is imperative
complex I in mammalian mitochondria. Molecular Cell, 13, 805–815.
to first unravel the metabolic escape routes harnessed by the cancer https://doi.org/10.1016/S1097-2765(04)00124-8
cells for their survival by maintaining a favorably reprogrammed RC‐ Ackrell, B. A. C. (2000). Progress in understanding structure‐function
OXPHOS function. In conclusion, mitochondrial RC alterations relationships in respiratory chain complex II. FEBS Letters, 466, 1–5.
appeared to be an integral component of tumorigenesis in concert https://doi.org/10.1016/S0014-5793(99)01749-4
Ahn, E. H., Hirohata, K., Kohrn, B. F., Fox, E. J., Chang, C. C., & Loeb, L. A.
with nuclear genetic alterations and ought to be examined in depth.
(2015). Detection of ultra‐rare mitochondrial mutations in breast
Precise molecular mapping of mitochondrial changes and delineating stem cells by duplex sequencing. PLoS One, 10, 0136216. https://
their causative role in OXPHOS‐associated diseases and cancer could doi.org/10.1371/journal.pone.0136216
potentially be paradigm shifting in developing better‐personalized Alhomidi, M. A., Vedicherla, B., Movva, S., Rao, P. K., Ahuja, Y. R., &
Hasan, Q. (2013). Mitochondrial D310 instability in Asian Indian
care. With the advent of integrative protegenomic and multiomics
breast cancer patients. Tumor Biology, 34, 2427–2432. https://doi.
approaches, we can envision and anticipate the development of RC‐ org/10.1007/s13277-013-0793-0
targeted therapeutics as well as biomarkers for a better management Allegretti, M., Klusch, N., Mills, D. J., Vonck, J., Kühlbrandt, W., &
of various mitochondrial disorders and cancers in the coming Davies, K. M. (2015). Horizontal membrane‐intrinsic α‐helices in the
decades. stator a‐subunit of an F‐type ATP synthase. Nature, 521, 237–240.
https://doi.org/10.1038/nature14185
Alonso, A., Martin, P., Albarran, C., Aguilera, B., Garcia, O., Guzman, A.,
A C KN O W L E D G M E N T S Oliva, H., & Sancho, M. (1997). Detection of somatic mutations in
This work was supported by the National Institutes of Health/ the mitochondrial DNA control region of colorectal and gastric
National Cancer Institute [CA204801, CA231925 (to S Singh) and tumors by heteroduplex and single‐strand conformation analysis.
Electrophoresis, 18, 682–685. https://doi.org/10.1002/elps.
CA185490, CA224306 (to AP Singh)] and the University of South
1150180504
Alabama, Mitchell Cancer Institute. Santanu Dasgupta acknowledges Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L.,
generous support from the University of South Alabama and Mitchell Hornig‐Do, H. T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I.,
Cancer Institute. Wassmer, E., McFarland, R., & Taylor, R. W. (2012). Recessive
germline SDHA and SDHB mutations causing leukodystrophy and
isolated mitochondrial complex II deficiency. Journal of Medical
CO NFL I CT OF INTERES T Genetics, 49, 569–567. https://doi.org/10.1136/jmedgenet-2012-
The authors declare no conflict of interest. 101146
Andreu, A. L., Bruno, C., Dunne, T. C., Tanji, K., Shanske, S., Sue, C. M.,
Krishna, S., Hadjigeorgiou, G. M., Shtilbans, A., Bonilla, E., &
ORCID
DiMauro, S. (1999). A nonsense mutation (G15059A) in the
Kunwar Somesh Vikramdeo https://orcid.org/0000-0002- cytochrome b gene in a patient with exercise intolerance and
6016-2672 myoglobinuria. Annals of Neurology, 45(1), 127–130. https://doi.org/
Ajay P. Singh http://orcid.org/0000-0003-3492-6330 10.1002/1531-8249(199901)45:1%3C127::AID-ART20%3E3.0.
CO;2-Y
Santanu Dasgupta http://orcid.org/0000-0002-1499-0039
Andreu, A. L., Hanna, M. G., Reichmann, H., Bruno, C., Penn, A. S., Tanji, K.,
Pallotti, F., Iwata, S., Bonilla, E., Lach, B., Morgan‐Hughes, J.,
REFERENCES Shanske, S., Sue, C. M., Pulkes, T., Siddiqui, A., Clark, J. B., Land, J.,
Abdulhag, U. N., Soiferman, D., Schueler‐Furman, O., Miller, C., Shaag, A., Iwata, M., Schaefer, J., & DiMauro, S. (1999). Exercise intolerance
Elpeleg, O., Edvardson, S., & Saada, A. (2015). Mitochondrial due to mutations in the cytochrome b gene of mitochondrial DNA.
complex IV deficiency, caused by mutated COX6B1, is associated New England Journal of Medicine, 341, 1037–1044. https://doi.org/
with encephalomyopathy, hydrocephalus and cardiomyopathy. 10.1056/nejm199909303411404
Ashton, T. M., Gillies McKenna, W., Kunz‐Schughart, L. A., & Higgins, G. S. Journal, 272, 3583–2592. https://doi.org/10.1111/j.1742-4658.
(2018). Oxidative phosphorylation as an emerging target in cancer 2005.04779.x
therapy. Clinical Cancer Research, 24, 2482–2490. https://doi.org/ Blakely, E. L., de Silva, R., King, A., Schwarzer, V., Harrower, T.,
10.1158/1078-0432.CCR-17-3070 Dawidek, G., Turnbull, D. M., & Taylor, R. W. (2005). LHON/MELAS
Azoulay‐Zohar, H., Israelson, A., Abu‐Hamad, S., & Shoshan‐Barmatz, V. overlap syndrome associated with a mitochondrial MTND1 gene
(2004). In self‐defence: Hexokinase promotes voltage‐dependent mutation. European Journal of Human Genetics, 13, 623–627. https://
anion channel closure and prevents mitochondria‐mediated apo- doi.org/10.1038/sj.ejhg.5201363
ptotic cell death. Biochemical Journal, 377, 347–355. https://doi.org/ Blanchi, C., Genova, M. L., Castelli, G. P., & Lenaz, G. (2004). The
10.1042/BJ20031465 mitochondrial respiratory chain is partially organized in a super-
Bajzikova, M., Kovarova, J., Coelho, A. R., Boukalova, S., Oh, S., complex assembly: Kinetic evidence using flux control analysis.
Rohlenova, K., Svec, D., Hubackova, S., Endaya, B., Judasova, K., Journal of Biological Chemistry, 279(35), 36562–36569. https://doi.
Bezawork‐Geleta, A., Kluckova, K., Chatre, L., Zobalova, R., org/10.1074/jbc.M405135200
Novakova, A., Vanova, K., Ezrova, Z., Maghzal, G. J., Bonora, E., Porcelli, A. M., Gasparre, G., Biondi, A., Ghelli, A., Carelli, V.,
Magalhaes Novais, S., … Neuzil, J. (2019). Reactivation of dihydroor- Baracca, A., Tallini, G., Martinuzzi, A., Lenaz, G., Rugolo, M., &
otate dehydrogenase‐driven pyrimidine biosynthesis restores tumor Romeo, G. (2006). Defective oxidative phosphorylation in thyroid
growth of Respiration‐Deficient cancer cells. Cell Metabolism, 29, oncocytic carcinoma is associated with pathogenic mitochondrial
399–416. https://doi.org/10.1016/j.cmet.2018.10.014 DNA mutations affecting complexes I and III. Cancer Research, 66,
Ballantine, S. P., & Boxer, D. H. (1986). Isolation and characterisation of a 6087–6096. https://doi.org/10.1158/0008-5472.CAN-06-0171
soluble active fragment of hydrogenase isoenzyme 2 from the Borek, A., Ekiert, R., & Osyczka, A. (2016). Molecular effects of
membranes of anaerobically grown Escherichia coli. European Journal mitochondrial mutations in cytochrome b of complex III and their
of Biochemistry, 156, 277–84. https://doi.org/10.1111/j.1432-1033. impact on the levels of free radical production. Postepy Biochemii,
1986.tb09578.x 62(2), 162–172.
Ballard, J. W. O., & Whitlock, M. C. (2004). The incomplete natural history van den Bosch, B. J. C., Gerards, M., Sluiter, W., Stegmann, A. P. A.,
of mitochondria. Molecular Ecology, 13, 729–744. https://doi.org/10. Jongen, E. L. C., Hellebrekers, D. M. E. I., Oegema, R.,
1046/j.1365-294X.2003.02063.x Lambrichs, E. H., Prokisch, H., Danhauser, K., Schoonderwoerd, K.,
Baracca, A., Barogi, S., Carelli, V., Lenaz, G., & Solaini, G. (2000). Catalytic de Coo, I. F. M., & Smeets, H. J. M. (2012). Defective NDUFA9 as a
activities of mitochondrial ATP synthase in patients with mitochon- novel cause of neonatally fatal complex I disease. Journal of Medical
drial DNA T8993G mutation in the ATPase 6 gene encoding subunit Genetics, 49, 10–15. https://doi.org/10.1136/jmedgenet-2011-
a. Journal of Biological Chemistry, 275, 4177–4182. https://doi.org/ 100466
10.1074/jbc.275.6.4177 Brandon, M. C., Lott, M. T., Nguyen, K. C., Spolim, S., Navathe, S. B.,
Barbosa‐Gouveia, S., González‐Vioque, E., Borges, F., Gutiérrez‐Solana, L., Baldi, P., & Wallace, D. C. (2005). MITOMAP: A human mitochon-
Wintjes, L., Kappen, A., Van Den Heuvel, L., Leis, R., Rodenburg, R., & drial genome database—2004 update. Nucleic Acids Research, 33,
Couce, M. L. (2019). Identification and characterization of new 611–613. https://doi.org/10.1093/nar/gki079
variants in FOXRED1 gene expands the clinical spectrum associated Brischigliaro, M., & Zeviani, M. (2021). Cytochrome c oxidase deficiency.
with mitochondrial complex I deficiency. Journal of Clinical Medicine, Biochimica et Biophysica Acta—Bioenergetics, 1862, 148335. https://
8, 1262. https://doi.org/10.3390/jcm8081262 doi.org/10.1016/j.bbabio.2020.148335
Bazán, S., Mileykovskaya, E., Mallampalli, V. K. P. S., Heacock, P., Brown, M. D., Torroni, A., Reckord, C. L., & Wallace, D. C. (1995).
Sparagna, G. C., & Dowhan, W. (2013). Cardiolipin‐dependent Phylogenetic analysis of Leber's hereditary optic neuropathy
reconstitution of respiratory supercomplexes from purified Saccha- mitochondrial DNA's indicates multiple independent occurrences
romyces cerevisiae complexes III and IV. Journal of Biological of the common mutations. Human Mutation, 6, 311–325. https://doi.
Chemistry, 288, 401–411. https://doi.org/10.1074/jbc.M112. org/10.1002/humu.1380060405
425876 Bruno, C., Martinuzzi, A., Tang, Y., Andreu, A. L., Pallotti, F., Bonilla, E.,
Belinsky, M. G., Cai, K. Q., Zhou, Y., Luo, B., Pei, J., Rink, L., & Shanske, S., Fu, J., Sue, C. M., Angelini, C., DiMauro, S., &
von Mehren, M. (2017). Succinate dehydrogenase deficiency in a Manfredi, G. (1999). A stop‐codon mutation in the human mtDNA
PDGFRA mutated GIST. BMC Cancer, 17, 512. https://doi.org/10. cytochrome c oxidase I gene disrupts the functional structure of
1186/s12885-017-3499-7 complex IV. American Journal of Human Genetics, 65, 611–620.
Bénit, P., Slama, A., Cartault, F., Giurgea, I., Chretien, D., Lebon, S., https://doi.org/10.1086/302546
Marsac, C., Munnich, A., Rötig, A., & Rustin, P. (2004). Mutant Budde, S. M. S., van den Heuvel, L. P. W. J., Smeets, R. J. P., Skladal, D.,
NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. Mayr, J. A., Boelen, C., Petruzzella, V., Papa, S., & Smeitink, J. A. M.
Journal of Medical Genetics, 41, 14–17. https://doi.org/10.1136/jmg. (2003). Clinical heterogeneity in patients with mutations in the
2003.014316 NDUFS4 gene of mitochondrial complex I. Journal of Inherited
Berger, I., Hershkovitz, E., Shaag, A., Edvardson, S., Saada, A., & Elpeleg, O. Metabolic Disease, 26, 813–815. https://doi.org/10.1023/B:BOLI.
(2008). Mitochondrial complex I deficiency caused by a deleterious 0000010003.14113.af
NDUFA11 mutation. Annals of Neurology, 63, 405–408. https://doi. Bugiani, M., Invernizzi, F., Alberio, S., Briem, E., Lamantea, E., Carrara, F.,
org/10.1002/ana.21332 Moroni, I., Farina, L., Spada, M., Donati, M. A., Uziel, G., & Zeviani, M.
Birkenmeier, K., Dröse, S., Wittig, I., Winkelmann, R., Käfer, V., Döring, C., (2004). Clinical and molecular findings in children with complex I
Hartmann, S., Wenz, T., Reichert, A. S., Brandt, U., & deficiency. Biochimica et Biophysica Acta—Bioenergetics, 1659,
Hansmann, M. L. (2016). Hodgkin and Reed‐Sternberg cells of 136–147. https://doi.org/10.1016/j.bbabio.2004.09.006
classical Hodgkin lymphoma are highly dependent on oxidative Calvo, S. E., Tucker, E. J., Compton, A. G., Kirby, D. M., Crawford, G.,
phosphorylation. International Journal of Cancer, 138, 2231–2246. Burtt, N. P., Rivas, M., Guiducci, C., Bruno, D. L., Goldberger, O. A.,
https://doi.org/10.1002/ijc.29934 Redman, M. C., Wiltshire, E., Wilson, C. J., Altshuler, D., Gabriel, S. B.,
Blakely, E. L., Mitchell, A. L., Fisher, N., Meunier, B., Nijtmans, L. G., Daly, M. J., Thorburn, D. R., & Mootha, V. K. (2010). High‐
Schaefer, A. M., Jackson, M. J., Turnbull, D. M., & Taylor, R. W. throughput, pooled sequencing identifies mutations in NUBPL and
(2005). A mitochondrial cytochrome b mutation causing severe FOXRED1 in human complex I deficiency. Nature Genetics, 42,
respiratory chain enzyme deficiency in humans and yeast. FEBS 851–858. https://doi.org/10.1038/ng.659
Campos, Y., García‐Redondo, A., Fernández‐Moreno, M. A., Martínez‐ (2008). Hexokinase II detachment from mitochondria triggers
Pardo, M., Goda, G., Rubio, J. C., Martín, M. A., Del Hoyo, P., apoptosis through the permeability transition pore independent of
Cabello, A., Bornstein, B., Garesse, R., & Arenas, J. (2001). Early‐ voltage‐dependent anion channels. PLoS One, 3, 1852. https://doi.
onset multisystem mitochondrial disorder caused by a nonsense org/10.1371/journal.pone.0001852
mutation in the mitochondrial DNA cytochrome C oxidase II gene. Chinnery, P. F., Brown, D. T., Andrews, R. M., Singh‐Kler, R., Riordan‐Eva,
Annals of Neurology, 50, 409–413. https://doi.org/10.1002/ P., Lindley, J., Applegarth, D. A., Turnbull, D. M., & Howell, N. (2001).
ana.1141 The mitochondrial ND6 gene is a hot spot for mutations that cause
Carelli, V., D'Adamo, P., Valentino, M. L., La Morgia, C., Ross‐Cisneros, F. Leber's hereditary optic neuropathy. Brain, 124, 209–218. https://
N., Caporali, L., Maresca, A., Polosa, P. L., Barboni, P., De Negri, A., doi.org/10.1093/brain/124.1.209
Sadun, F., Karanjia, R., Salomao, S. R., Berezovsky, A., Chicani, F., Chomyn, A., Cleeter, M. W. J., Ian Ragan, C., Riley, M., Doolittle, R. F., &
Moraes, M., Filho, M. M., Belfort, R., & Sadun, A. A. (2016). Parsing Attardi, G. (1986). URF6, last unidentified reading frame of human
the differences in affected with LHON: Genetic versus environ- mtDNA, codes for an NADH dehydrogenase subunit. Science, 234,
mental triggers of disease conversion. Brain, 139, e17. https://doi. 614–618. https://doi.org/10.1126/science.3764430
org/10.1093/brain/awv339 Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno‐Yagi, A.,
Caro, P., Kishan, A. U., Norberg, E., Stanley, I. A., Chapuy, B., Ficarro, S. B., Hatefi, Y., Doolittle, R. F., & Attardi, G. (1985). Six unidentified
Polak, K., Tondera, D., Gounarides, J., Yin, H., Zhou, F., Green, M. R., reading frames of human mitochondrial DNA encode components of
Chen, L., Monti, S., Marto, J. A., Shipp, M. A., & Danial, N. N. (2012). the respiratory‐chain NADH dehydrogenase. Nature, 314, 592–597.
Metabolic signatures uncover distinct targets in molecular subsets of https://doi.org/10.1038/314592a0
diffuse large B cell lymphoma. Cancer Cell, 22, 547–560. https://doi. Clark, K. M., Taylor, R. W., Johnson, M. A., Chinnery, P. F., Chrzanowska‐
org/10.1016/j.ccr.2012.08.014 Lightowlers, Z. M. A., Andrews, R. M., Nelson, I. P., Wood, N. W.,
Carossa, V., Ghelli, A., Tropeano, C. V., Valentino, M. L., Iommarini, L., Lamont, P. J., Hanna, M. G., Lightowlers, R. N., & Turnbull, D. M.
Maresca, A., Caporali, L., La Morgia, C., Liguori, R., Barboni, P., (1999). An mtDNA mutation in the initiation codon of the
Carbonelli, M., Rizzo, G., Tonon, C., Lodi, R., Martinuzzi, A., cytochrome C oxidase subunit II gene results in lower levels of the
De Nardo, V., Rugolo, M., Ferretti, L., Gandini, F., … Carelli, V. protein and a mitochondrial encephalomyopathy. American Journal of
(2014). A novel in‐frame 18‐bp microdeletion in MT‐CYB causes a Human Genetics, 64, 1330–1339. https://doi.org/10.1086/302361
multisystem disorder with prominent exercise intolerance. Human Comi, G. P., Bordoni, A., Salani, S., Franceschina, L., Sciacco, M., Prelle, A.,
Mutation, 35, 954–958. https://doi.org/10.1002/humu.22596 Fortunato, F., Zeviani, M., Napoli, L., Bresolin, N., Moggio, M.,
Carrera, S., Beristain, E., Sancho, A., Iruarrizaga, E., Rivero, P., Mañe, J. M., Ausenda, C. D., Taanman, J. W., & Scarlato, G. (1998). Cytochrome c
& López Vivanco, G. (2019). Germline c.1A>C heterozygous oxidase subunit I microdeletion in a patient with motor neuron
pathogenic variant in SDHA reported for the first time in a young disease. Annals of Neurology, 43, 110–116. https://doi.org/10.1002/
adult with a gastric gastrointestinal stromal tumour (GIST): A case ana.410430119
report. Hereditary Cancer in Clinical Practice, 17, 23. https://doi.org/ De Coo, I. F. M., Renier, W. O., Ruitenbeek, W., Ter Laak, H. J., Bakker, M.,
10.1186/s13053-019-0124-6 Schägger, H., Van Oost, B. A., & Smeets, H. J. M. (1999). A 4‐base
Carroll, J., Fearnley, I. M., Shannon, R. J., Hirst, J., & Walker, J. E. (2003). pair deletion in the mitochondrial cytochrome b gene associated
Analysis of the subunit composition of complex I from bovine heart with Parkinsonism/MELAS overlap syndrome. Annals of Neurology,
mitochondria. Molecular & Cellular Proteomics: MCP, 2, 117–126. 45(1), 130–133. https://doi.org/10.1002/1531-8249(199901)
https://doi.org/10.1074/mcp.M300014-MCP200 45:1%3C130::AID-ART21%3E3.0.CO;2-Z
Carrozzo, R., Murray, J., Santorelli, F. M., & Capaldi, R. A. (2000). The Craven, L., Alston, C. L., Taylor, R. W., & Turnbull, D. M. (2017). Recent
T9176G mutation of human mtDNA gives a fully assembled but advances in mitochondrial disease. Annual Review of Genomics and
inactive ATP synthase when modeled in Escherichia coli. FEBS Letters, Human Genetics, 18, 257–275. https://doi.org/10.1146/annurev-
486, 297–299. https://doi.org/10.1016/S0014-5793(00)02244-4 genom-091416-035426
Casey, R. T., Ascher, D. B., Rattenberry, E., Izatt, L., Andrews, K. A., Cruz‐Bermúdez, A., Vallejo, C. G., Vicente‐Blanco, R. J., Gallardo, M. E.,
Simpson, H. L., Challis, B., Park, S. M., Bulusu, V. R., Lalloo, F., Fernández‐Moreno, M. Á., Quintanilla, M., & Garesse, R. (2015).
Pires, D. E. V., West, H., Clark, G. R., Smith, P. S., Whitworth, J., Enhanced tumorigenicity by mitochondrial DNA mild mutations.
Papathomas, T. G., Taniere, P., Savisaar, R., Hurst, L. D., … Oncotarget, 6, 13628–13643. https://doi.org/10.18632/
Maher, E. R. (2017). SDHA related tumorigenesis: A new case series oncotarget.3698
and literature review for variant interpretation and pathogenicity. Dasgupta, S., Hoque, M. O., Upadhyay, S., & Sidransky, D. (2008).
Molecular Genetics and Genomic Medicine, 5, 237–250. https://doi. Mitochondrial cytochrome B gene mutation promotes tumor growth
org/10.1002/mgg3.279 in bladder cancer. Cancer Research, 68, 700–706. https://doi.org/10.
Cecchini, G. (2003). Function and structure of complex II of the 1158/0008-5472.CAN-07-5532
respiratory chain. Annual Review of Biochemistry, 72, 77–109. Dasgupta, S., Hoque, M. O., Upadhyay, S., & Sidransky, D. (2009). Forced
https://doi.org/10.1146/annurev.biochem.72.121801.161700 cytochrome B gene mutation expression induces mitochondrial
Chandel, N. S. (2010). Mitochondrial complex III: An essential component proliferation and prevents apoptosis in human uroepithelial SV‐
of universal oxygen sensing machinery? Respiratory Physiology and HUC‐1 cells. International Journal of Cancer, 125, 2829–2835.
Neurobiology, 174, 175–181. https://doi.org/10.1016/j.resp.2010. https://doi.org/10.1002/ijc.24701
08.004 Dasgupta, S., Shao, C., Keane, T. E., Duberow, D. P., Mathies, R. A.,
Chatterjee, A., Dasgupta, S., & Sidransky, D. (2011). Mitochondrial Fisher, P. B., Kiemeney, L. A., & Sidransky, D. (2012). Detection of
subversion in cancer. Cancer Prevention Research, 4, 638–654. mitochondrial deoxyribonucleic acid alterations in urine from
https://doi.org/10.1158/1940-6207.CAPR-10-0326 urothelial cell carcinoma patients. International Journal of Cancer,
Chen, Y., Cairns, R., Papandreou, I., Koong, A., & Denko, N. C. (2009). 131, 158–164. https://doi.org/10.1002/ijc.26357
Oxygen consumption can regulate the growth of tumors, a new Dasgupta, S., Soudry, E., Mukhopadhyay, N., Shao, C., Yee, J., Lam, S.,
perspective on the Warburg effect. PLoS One, 4, e7033. https://doi. Lam, W., Zhang, W., Gazdar, A. F., Fisher, P. B., & Sidransky, D.
org/10.1371/journal.pone.0007033 (2012). Mitochondrial DNA mutations in respiratory complex‐I in
Chiara, F., Castellaro, D., Marin, O., Petronilli, V., Brusilow, W. S., never‐smoker lung cancer patients contribute to lung cancer
Juhaszova, M., Sollott, S. J., Forte, M., Bernardi, P., & Rasola, A. progression and associated with EGFR gene mutation. Journal of
Cellular Physiology, 227, 2451–2460. https://doi.org/10.1002/jcp. Ferreira, M., Torraco, A., Rizza, T., Fattori, F., Meschini, M. C., Castana, C.,
22980 Go, N. E., Nargang, F. E., Duarte, M., Piemonte, F., Dionisi‐Vici, C.,
Dasgupta, S., Yung, R. C., Westra, W. H., Rini, D. A., Brandes, J., & Videira, A., Vilarinho, L., Santorelli, F. M., Carrozzo, R., & Bertini, E.
Sidransky, D. (2009). Following mitochondrial footprints through a (2011). Progressive cavitating leukoencephalopathy associated with
long mucosal path to lung cancer. PLoS One, 4, 6533. https://doi. respiratory chain complex I deficiency and a novel mutation in
org/10.1371/journal.pone.0006533 NDUFS1. Neurogenetics, 12, 9–17. https://doi.org/10.1007/
Deschauer, M., Bamberg, C., Claus, D., Zierz, S., Turnbull, D. M., & s10048-010-0265-2
Taylor, R. W. (2003). Late‐onset encephalopathy associated with a Finsterer, J., Mancuso, M., Pareyson, D., Burgunder, J. M., & Klopstock, T.
C11777A mutation of mitochondrial DNA. Neurology, 60, 1357–1359. (2018). Mitochondrial disorders of the retinal ganglion cells and the
https://doi.org/10.1212/01.WNL.0000055869.99975.4B optic nerve. Mitochondrion, 42, 1–10. https://doi.org/10.1016/j.
Dickson, V. K., Silvester, J. A., Fearnley, I. M., Leslie, A. G. W., & mito.2017.10.003
Walker, J. E. (2006). On the structure of the stator of the Fisher, N., & Meunier, B. (2001). Effects of mutations in mitochondrial
mitochondrial ATP synthase. The EMBO Journal, 25, 2911–2918. cytochrome b in yeast and man: Deficiency, compensation and
https://doi.org/10.1038/sj.emboj.7601177 disease. European Journal of Biochemistry, 268, 1155–1162. https://
Dionisi‐Vici, C., Seneca, S., Zeviani, M., Fariello, G., Rlmoldi, M., Bertini, E., doi.org/10.1046/j.1432-1327.2001.02010.x
& De Meirleir, L. (1998). Fulminant Leigh syndrome and sudden Friedrich, T., & Scheide, D. (2000). The respiratory complex I of bacteria,
unexpected death in a family with the T9176C mutation of the archaea and eukarya and its module common with membrane‐bound
mitochondrial ATPase 6 gene. Journal of Inherited Metabolic Disease, multisubunit hydrogenases. FEBS Letters, 479, 1–5. https://doi.org/
21, 2–8. https://doi.org/10.1023/A:1005397227996 10.1016/S0014-5793(00)01867-6
Duberow, D. P., Brait, M., Hoque, M. O., Theodorescu, D., Sidransky, D., Friedrich, T., & Böttcher, B. (2004). The gross structure of the respiratory
Dasgupta, S., & Mathies, R. A. (2016). High‐performance detection complex I: A lego system. Biochimica et Biophysica Acta—
of somatic D‐loop mutation in urothelial cell carcinoma patients by Bioenergetics, 1608, 1–9. https://doi.org/10.1016/j.bbabio.2003.
polymorphism ratio sequencing. Journal of Molecular Medicine, 94, 10.002
1015–1024. https://doi.org/10.1007/s00109-016-1407-2 Gai, Z., Matsuno, A., Kato, K., Kato, S., Khan, M. R. I., Shimizu, T.,
Dunning, C. J. R., McKenzie, M., Sugiana, C., Lazarou, M., Silke, J., Yoshioka, T., Kato, Y., Kishimura, H., Kanno, G., Miyabe, Y.,
Connelly, A., Fletcher, J. M., Kirby, D. M., Thorburn, D. R., & Terada, T., Tanaka, Y., & Yao, M. (2015). Crystal structure of the
Ryan, M. T. (2007). Human CIA30 is involved in the early assembly 3.8‐MDa respiratory supermolecule hemocyanin at 3.0 Å resolution.
of mitochondrial complex I and mutations in its gene cause disease. Structure, 23, 2204–2212. https://doi.org/10.1016/j.str.2015.
The EMBO Journal, 26, 3227–3237. https://doi.org/10.1038/sj. 09.008
emboj.7601748 Gaignard, P., Menezes, M., Schiff, M., Bayot, A., Rak, M.,
Emmanuele, V., Sotiriou, E., Rios, P. G., Ganesh, J., Ichord, R., Foley, A. R., Ogier De Baulny, H., Su, C. H., Gilleron, M., Lombes, A., Abida, H.,
Akman, H. O., & Dimauro, S. (2013). A novel mutation in the Tzagoloff, A., Riley, L., Cooper, S. T., Mina, K., Sivadorai, P.,
mitochondrial DNA cytochrome b gene (MTCYB) in a patient with Davis, M. R., Allcock, R. J., Kresoje, N., Laing, N. G., … Rustin, P.
mitochondrial encephalomyopathy, lactic acidosis, and strokelike (2013). Mutations in CYC1, encoding cytochrome c1 subunit of
episodes syndrome. Journal of Child Neurology, 28, 236–242. https:// respiratory chain complex III, cause insulin‐responsive hyper-
doi.org/10.1177/0883073812445787 glycemia. American Journal of Human Genetics, 93, 384–389.
Engvall, M., Kawasaki, A., Carelli, V., Wibom, R., Bruhn, H., Lesko, N., https://doi.org/10.1016/j.ajhg.2013.06.015
Schober, F. A., Wredenberg, A., Wedell, A., & Träisk, F. (2021). Case García, J. J., Ogilvie, I., Robinson, B. H., & Capaldi, R. A. (2000). Structure,
report: A novel mutation in the mitochondrial MT‐ND5 gene functioning, and assembly of the ATP synthase in cells from patients
is associated with leber hereditary optic neuropathy (LHON). with the T8993G mitochondrial DNA mutation. Comparison with the
Frontiers in Neurology, 12, 652590. https://doi.org/10.3389/fneur. enzyme in Rho cells completely lacking mtDNA. Journal of Biological
2021.652590 Chemistry, 275, 11075–11081. https://doi.org/10.1074/jbc.275.15.
Eubel, H., Heinemeyer, J., Sunderhaus, S., & Braun, H. P. (2004). 11075
Respiratory chain supercomplexes in plant mitochondria. Plant Gattermann, N., Retzlaff, S., Wang, Y. L., Hofhaus, G., Heinisch, J., Aul, C.,
Physiology and Biochemistry, 42, 937–942. https://doi.org/10. & Schneider, W. (1997). Heteroplasmic point mutations of mito-
1016/j.plaphy.2004.09.010 chondrial DNA affecting subunit I of cytochrome c oxidase in two
Fedor, J. G., & Hirst, J. (2018). Mitochondrial supercomplexes do not patients with acquired idiopathic sideroblastic anemia. Blood, 90,
enhance catalysis by quinone channeling. Cell Metabolism, 28, 4961–4972. https://doi.org/10.1182/blood.v90.12.4961.4961_
525–531. https://doi.org/10.1016/j.cmet.2018.05.024 4961_4972
Ferguson, L. R., Chen, H., Collins, A. R., Connell, M., Damia, G., Gaude, E., & Frezza, C. (2016). Tissue‐specific and convergent metabolic
Dasgupta, S., Malhotra, M., Meeker, A. K., Amedei, A., Amin, A., transformation of cancer correlates with metastatic potential and
Ashraf, S. S., Aquilano, K., Azmi, A. S., Bhakta, D., Bilsland, A., patient survival. Nature Communications, 7, 13041. https://doi.org/
Boosani, C. S., Chen, S., Ciriolo, M. R., Fujii, H., … Maxwell, C. A. 10.1038/ncomms13041
(2015). Genomic instability in human cancer: Molecular insights and Gault, M. D., Mandelker, D., Delair, D., Stewart, C. R., Kemel, Y.,
opportunities for therapeutic attack and prevention through diet and Sheehan, M. R., Siegel, B., Kennedy, J., Marcell, V., Arnold, A., Al‐
nutrition. Seminars in Cancer Biology, 35 Suppl, S5–S24. https://doi. Ahmadie, H., Modak, S., Robson, M., Shukla, N., Roberts, S., Vijai, J.,
org/10.1016/j.semcancer.2015.03.005 Topka, S., Kentsis, A., Cadoo, K., & Walsh, M. F. (2018). Germline
Fernandez‐Moreira, D., Ugalde, C., Smeets, R., Rodenburg, R. J. T., Lopez‐ SDHA mutations in children and adults with cancer. Cold Spring
Laso, E., Ruiz‐Falco, M. L., Briones, P., Martin, M. A., Harbor Molecular Case Studies, 4, a002584. https://doi.org/10.1101/
Smeitink, J. A. M., & Arenas, J. (2007). X‐linked NDUFA1 gene mcs.a002584
mutations associated with mitochondrial encephalomyopathy. Ghosh, P., Vidal, C., Dey, S., & Zhang, L. (2020). Mitochondria targeting as an
Annals of Neurology, 61, 73–83. https://doi.org/10.1002/ana.21036 effective strategy for cancer therapy. International Journal of Molecular
Fernández‐Vizarra, E., & Zeviani, M. (2015). Nuclear gene mutations as Sciences, 21, 3363. https://doi.org/10.3390/ijms21093363
the cause of mitochondrial complex III deficiency. Frontiers in González‐Quintana, A., García‐Consuegra, I., Belanger‐Quintana, A.,
Genetics, 6, 134. https://doi.org/10.3389/fgene.2015.00134 Serrano‐Lorenzo, P., Lucia, A., Blázquez, A., Docampo, J.,
Ugalde, C., Morán, M., Arenas, J., & Martín, M. A. (2020). Novel The FEBS Letters, 344, 15–19. https://doi.org/10.1016/0014-
ndufa13 mutations associated with oxphos deficiency and leigh 5793(94)00346-7
syndrome: A second family report. Genes, 11, 855. https://doi.org/ Hertweck, K. L., & Dasgupta, S. (2017). The landscape of mtDNA
10.3390/genes11080855 modifications in cancer: A tale of two cities. Frontiers in Oncology, 7,
Grazioli, S., & Pugin, J. (2018). Mitochondrial damage‐associated molecu- 262. https://doi.org/10.3389/fonc.2017.00262
lar patterns: From inflammatory signaling to human diseases. Hirst, J. (2018). Open questions: Respiratory chain supercomplexes‐why
Frontiers in Immunology, 9, 832. https://doi.org/10.3389/fimmu. are they there and what do they do? BMC Biology, 16, 111. https://
2018.00832 doi.org/10.1186/s12915-018-0577-5
Greggio, C., Jha, P., Kulkarni, S. S., Lagarrigue, S., Broskey, N. T., Hirst, J., Carroll, J., Fearnley, I. M., Shannon, R. J., & Walker, J. E. (2003).
Boutant, M., Wang, X., Conde Alonso, S., Ofori, E., Auwerx, J., The nuclear encoded subunits of complex I from bovine heart
Cantó, C., & Amati, F. (2017). Enhanced respiratory chain super- mitochondria. Biochimica et Biophysica Acta—Bioenergetics, 1604,
complex formation in response to exercise in human skeletal muscle. 135–150. https://doi.org/10.1016/S0005-2728(03)00059-8
Cell Metabolism, 25, 301–311. https://doi.org/10.1016/j.cmet.2016. Hoefs, S. J. G., Dieteren, C. E. J., Distelmaier, F., Janssen, R. J. R. J.,
11.004 Epplen, A., Swarts, H. G. P., Forkink, M., Rodenburg, R. J.,
Grzybowska‐Szatkowska, L., Ślaska, B., Rzymowska, J., Brzozowska, A., & Nijtmans, L. G., Willems, P. H., Smeitink, J. A. M., &
Floriańczyk, B. (2014). Novel mitochondrial mutations in the ATP6 van den Heuvel, L. P. (2008). NDUFA2 complex I mutation leads
and ATP8 genes in patients with breast cancer. Molecular Medicine to Leigh disease. American Journal of Human Genetics, 82,
Reports, 10, 1772–1778. https://doi.org/10.3892/mmr.2014.2471 1306–1315. https://doi.org/10.1016/j.ajhg.2008.05.007
Gusic, M., Schottmann, G., Feichtinger, R. G., Du, C., Scholz, C., Hollinshead, K. E. R., Parker, S. J., Eapen, V. V., Encarnacion‐Rosado, J.,
Wagner, M., Mayr, J. A., Lee, C. Y., Yépez, V. A., Lorenz, N., Sohn, A., Oncu, T., Cammer, M., Mancias, J. D., & Kimmelman, A. C.
Morales‐Gonzalez, S., Panneman, D. M., Rötig, A., (2020). Respiratory supercomplexes promote mitochondrial effi-
Rodenburg, R. J. T., Wortmann, S. B., Prokisch, H., & Schuelke, M. ciency and growth in severely hypoxic pancreatic cancer. Cell
(2020). Bi‐allelic UQCRFS1 variants are associated with mitochon- Reports, 33, 108231. https://doi.org/10.1016/j.celrep.2020.108231
drial complex III deficiency, cardiomyopathy, and alopecia totalis. Holme, E., Greter, J., Jacobson, C. E., Larsson, N. G., Lindstedt, S.,
American Journal of Human Genetics, 106, 102–111. https://doi.org/ Nilsson, K. O., Oldfors, A., & Tulinius, M. (1992). Mitochondrial ATP‐
10.1016/j.ajhg.2019.12.005 synthase deficiency in a child with 3‐methylglutaconic aciduria.
Haack, T. B., Madignier, F., Herzer, M., Lamantea, E., Danhauser, K., Pediatric Research, 32, 731–735. https://doi.org/10.1203/
Invernizzi, F., Koch, J., Freitag, M., Drost, R., Hillier, I., 00006450-199212000-00022
Haberberger, B., Mayr, J. A., Ahting, U., Tiranti, V., Rötig, A., Holt, I. J., Harding, A. E., Petty, R. K. H., & Morgan‐Hughes, J. A. (1990). A
Iuso, A., Horvath, R., Tesarova, M., Baric, I., … Prokisch, H. (2012). new mitochondrial disease associated with mitochondrial DNA
Mutation screening of 75 candidate genes in 152 complex I heteroplasmy. American Journal of Human Genetics, 46, 428–433.
deficiency cases identifies pathogenic variants in 16 genes including Hoogenraad, N. J., Ward, L. A., & Ryan, M. T. (2002). Import and assembly
NDUFB9. Journal of Medical Genetics, 49, 83–89. https://doi.org/10. of proteins into mitochondria of mammalian cells. Biochimica et
1136/jmedgenet-2011-100577 Biophysica Acta—Molecular Cell Research, 1592, 97–105. https://doi.
Hagen, C. M., Aidt, F. H., Havndrup, O., Hedley, P. L., Jespersgaard, C., org/10.1016/S0167-4889(02)00268-9
Jensen, M., Kanters, J. K., Moolman‐Smook, J. C., Møller, D. V., Hopkins, J. F., Denroche, R. E., Aguiar, J. A., Notta, F., Connor, A. A.,
Bundgaard, H., & Christiansen, M. (2013). Mt‐cyb mutations in Wilson, J. M., Stein, L. D., Gallinger, S., & Boutros, P. C. (2018).
hypertrophic cardiomyopathy. Molecular Genetics and Genomic Mutations in mitochondrial DNA from pancreatic ductal adenocar-
Medicine, 1, 54–65. https://doi.org/10.1002/mgg3.5 cinomas associate with survival times of patients and accumulate as
Hägerhäll, C. (1997). Succinate: Quinone oxidoreductases. Variations on a tumors progress. Gastroenterology, 154, 1620–1624. https://doi.
conserved theme. Biochimica et Biophysica Acta—Bioenergetics, 1320, org/10.1053/j.gastro.2018.01.029
107–141. https://doi.org/10.1016/S0005-2728(97)00019-4 Hopkins, J. F., Sabelnykova, V. Y., Weischenfeldt, J., Simon, R.,
Hamvas, A., Corradi, G., Hegedüs, M., & Frang, D. (1991). Experience with Aguiar, J. A., Alkallas, R., Heisler, L. E., Zhang, J., Watson, J. D.,
the Peponen® capsule in the management of benign prostatic Chua, M., Fraser, M., Favero, F., Lawerenz, C., Plass, C., Sauter, G.,
hyperplasia. International Urology and Nephrology, 23, 51–55. McPherson, J. D., Van Der Kwast, T., Korbel, J., Schlomm, T., …
https://doi.org/10.1007/BF02549728 Boutros, P. C. (2017). Mitochondrial mutations drive prostate cancer
Hanna, M. G., Nelson, I. P., Rahman, S., Lane, R. J. M., Land, J., Heales, S., aggression. Nature Communications, 8, 656. https://doi.org/10.
Cooper, M. J., Schapira, A. H. V., Morgan‐Hughes, J. A., & 1038/s41467-017-00377-y
Wood, N. W. (1998). Cytochrome c oxidase deficiency associated Horváth, R., Schoser, B. G. H., Müller‐Höcker, J., Völpel, M., Jaksch, M., &
with the first stop‐codon point mutation in human mtDNA. American Lochmüller, H. (2005). Mutations in mtDNA‐encoded cytochrome c
Journal of Human Genetics, 63, 29–36. https://doi.org/10.1086/ oxidase subunit genes causing isolated myopathy or severe
301910 encephalomyopathy. Neuromuscular Disorders, 15, 851–857.
He, I., Luo, L., Proctor, S. J., Middleton, P. G., Blakely, E. L., Taylor, R. W., & https://doi.org/10.1016/j.nmd.2005.09.005
Turnbull, D. M. (2003). Somatic mitochondrial DNA mutations in Howell, N., Bogolin, C., Jamieson, R., Marenda, D. R., & Mackey, D. A.
adult‐onset leukaemia. Leukemia, 17, 2487–2491. https://doi.org/ (1998). mtDNA mutations that cause optic neuropathy: How do we
10.1038/sj.leu.2403146 know? American Journal of Human Genetics, 62, 196–202. https://
He, X., Zhou, A., Lu, H., Chen, Y., Huang, G., Yue, X., Zhao, P., & Wu, Y. doi.org/10.1086/301675
(2013). Suppression of mitochondrial complex I influences cell Huang, Y. C., Chang, H. H., Chen, M. H., Huang, K. H., Li, A. F. Y., Lin, C. H.,
metastatic properties. PLoS One, 8(4), e61677. https://doi.org/10. Shyr, Y. M., & Fang, W. L. (2020). Somatic SDHA mutations in
1371/journal.pone.0061677 paragangliomas in siblings: Case report of 2 cases. Medicine, 99(41),
Hemrika, W., Lobo‐Hajdu, G., Berden, J. A., & Grivell, L. A. (1994). The e22497. https://doi.org/10.1097/MD.0000000000022497
aromatic nature of residue 66 of the 11‐kDa subunit of ubiquinol‐ Hunte, C., Koepke, J., Lange, C., Roßmanith, T., & Michel, H. (2000).
cytochrome c oxidoreductase of the yeast Saccharomyces Structure at 2.3 Å resolution of the cytochrome bc1 complex from
cerevisiae is important for the assembly of a functional enzyme. the yeast Saccharomyces cerevisiae co‐crystallized with an antibody
Fv fragment. Structure, 8, 669–684. https://doi.org/10.1016/ & Zacksenhaus, E. (2016). RB1 deficiency in triple‐negative breast
S0969-2126(00)00152-0 cancer induces mitochondrial protein translation. Journal of Clinical
Hunte, C., Zickermann, V., & Brandt, U. (2010). Functional modules and Investigation, 126, 3739–3757. https://doi.org/10.1172/JCI81568
structural basis of conformational coupling basis of conformational Kadenbach, B., & Hüttemann, M. (2015). The subunit composition and
coupling in mitochondrial complex I. Science, 329, 448–451. https:// function of mammalian cytochrome c oxidase. Mitochondrion, 24,
doi.org/10.1126/science.1191046 64–76. https://doi.org/10.1016/j.mito.2015.07.002
Invernizzi, F., Tigano, M., Dallabona, C., Donnini, C., Ferrero, I., Kampjut, D., & Sazanov, L. A. (2020). The coupling mechanism of
Cremonte, M., Ghezzi, D., Lamperti, C., & Zeviani, M. (2013). A mammalian respiratory complex I. Science, 370, eabc4209. https://
homozygous mutation in LYRM7/MZM1L associated with early doi.org/10.1126/SCIENCE.ABC4209
onset encephalopathy, lactic acidosis, and severe reduction of Karadimas, C. L., Greenstein, P., Sue, C. M., Joseph, J. T., Tanji, K.,
mitochondrial complex III activity. Human Mutation, 34, Haller, R. G., Taivassalo, T., Davidson, M. M., Shanske, S., Bonilla, E.,
1619–1622. https://doi.org/10.1002/humu.22441 & DiMauro, S. (2000). Recurrent myoglobinuria due to a nonsense
Iommarini, L., Ghelli, A., Tropeano, C. V., Kurelac, I., Leone, G., Vidoni, S., mutation in the COX I gene of mitochondrial DNA. Neurology, 55,
Lombes, A., Zeviani, M., Gasparre, G., & Porcelli, A. M. (2018). 644–649. https://doi.org/10.1212/WNL.55.5.644
Unravelling the effects of the mutation m.3571insC/MT‐ND1 on Keightley, J. A., Anitori, R., Burton, M. D., Quan, F., Buist, N. R. M., &
respiratory complexes structural organization. International Journal Kennaway, N. G. (2000). Mitochondrial encephalomyopathy and
of Molecular Sciences, 19(3), 764. https://doi.org/10.3390/ complex III deficiency associated with a stop‐codon mutation in the
ijms19030764 cytochrome b gene. American Journal of Human Genetics, 67,
Ishikawa, K., Takenaga, K., Akimoto, M., Koshikawa, N., Yamaguchi, A., 1400–1410. https://doi.org/10.1086/316900
Imanishi, H., Nakada, K., Honma, Y., & Hayashi, J. I. (2008). ROS‐ Khan, M. A., Zubair, H., Anand, S., Srivastava, S. K., Singh, S., & Singh, A. P.
generating mitochondrial DNA mutations can regulate tumor cell (2020). Dysregulation of metabolic enzymes in tumor and stromal
metastasis. Science, 320, 661–664. https://doi.org/10.1126/science. cells: Role in oncogenesis and therapeutic opportunities. Cancer
1156906 Letters, 473, 176–185. https://doi.org/10.1016/j.canlet.2020.01.003
Iuso, A., Scacco, S., Piccoli, C., Bellomo, F., Petruzzella, V., Trentadue, R., Kirby, D. M., McFarland, R., Ohtake, A., Dunning, C., Ryan, M. T.,
Minuto, M., Ripoli, M., Capitanio, N., Zeviani, M., & Papa, S. (2006). Wilson, C., Ketteridge, D., Turnbull, D. M., Thorburn, D. R., &
Dysfunctions of cellular oxidative metabolism in patients with Taylor, R. W. (2004). Mutations of the mitochondrial ND1 gene as a
mutations in the NDUFS1 and NDUFS4 genes of complex I. cause of MELAS. Journal of Medical Genetics, 41, 784–789. https://
Journal of Biological Chemistry, 281, 10374–10380. https://doi.org/ doi.org/10.1136/jmg.2004.020537
10.1074/jbc.M513387200 Kirby, D. M., Salemi, R., Sugiana, C., Ohtake, A., Parry, L., Bell, K. M.,
Iwata, S., Lee, J. W., Okada, K., Lee, J. K., Iwata, M., Rasmussen, B., Kirk, E. P., Boneh, A., Taylor, R. W., Dahl, H. H. M., Ryan, M. T., &
Link, T. A., Ramaswamy, S., & Jap, B. K. (1998). Complete structure Thorburn, D. R. (2004). NDUFS6 mutations are a novel cause of
of the 11‐subunit bovine mitochondrial cytochrome bc1 complex. lethal neonatal mitochondrial complex I deficiency. Journal of Clinical
Science, 281, 64–71. https://doi.org/10.1126/science.281.5373.64 Investigation, 114, 837–845. https://doi.org/10.1172/JCI20683
Jackson, C. B., Hahn, D., Schröter, B., Richter, U., Battersby, B. J., Schmitt‐ Kishita, Y., Ishikawa, K., Nakada, K., Hayashi, J. I., Fushimi, T., Shimura, M.,
Mechelke, T., Marttinen, P., Nuoffer, J. M., & Schaller, A. (2017). A Kohda, M., Ohtake, A., Murayama, K., & Okazaki, Y. (2021). A high
novel mitochondrial ATP6 frameshift mutation causing isolated mutation load of m.14597A>G in MT‐ND6 causes Leigh syndrome.
complex V deficiency, ataxia and encephalomyopathy. European Scientific Reports, 11, 11123. https://doi.org/10.1038/s41598-021-
Journal of Medical Genetics, 60, 345–351. https://doi.org/10.1016/j. 90196-5
ejmg.2017.04.006 Kollberg, G., Moslemi, A. R., Lindberg, C., Holme, E., & Oldfors, A. (2005).
Jain‐Ghai, S., Cameron, J. M., Al Maawali, A., Blaser, S., Mackay, N., Mitochondrial myopathy and rhabdomyolysis associated with a
Robinson, B., & Raiman, J. (2013). Complex II deficiency—A case novel nonsense mutation in the gene encoding cytochrome c
report and review of the literature. American Journal of Medical oxidase subunit I. Journal of Neuropathology and Experimental
Genetics, Part A, 161A, 285–294. https://doi.org/10.1002/ajmg.a. Neurology, 64, 123–128. https://doi.org/10.1093/jnen/64.2.123
35714 Korpershoek, E., Favier, J., Gaal, J., Burnichon, N., Van Gessel, B.,
Janssen, R. J. R. J., Nijtmans, L. G., van den Heuvel, L. P., & Oudijk, L., Badoual, C., Gadessaud, N., Venisse, A., Bayley, J. P.,
Smeitink, J. A. M. (2006). Mitochondrial complex I: Structure, Van Dooren, M. F., De Herder, W. W., Tissier, F., Plouin, P. F.,
function and pathology. Journal of Inherited Metabolic Disease, 29, Van Nederveen, F. H., Dinjens, W. N. M., Gimenez‐Roqueplo, A. P.,
499–515. https://doi.org/10.1007/s10545-006-0362-4 & De Krijger, R. R. (2011). SDHA immunohistochemistry detects
Jiang, H., Duan, K., Han, X., Wang, J., Liu, X., Yan, M., Wang, Y., Liu, H., germline SDHA gene mutations in apparently sporadic paraganglio-
Shi, H., Gao, X., Ouyang, C., Fu, X., Zhang, X., & Liu, C. (2021). mas and pheochromocytomas. Journal of Clinical Endocrinology and
Detection of mitochondrial mutations through isothermal nucleic Metabolism, 96, 1472–1476. https://doi.org/10.1210/jc.2011-1043
acid amplification coupled with clustered regularly interspaced short Kühlbrandt, W. (2015). Structure and function of mitochondrial mem-
palindromic repeat‐associated endonuclease Cas13a. Frontiers in brane protein complexes. BMC Biology, 13, 89. https://doi.org/10.
Genetics, 11, 622671. https://doi.org/10.3389/fgene.2020.622671 1186/s12915-015-0201-x
Johns, D. R., Neufeld, M. J., & Hedges, T. R. (1994). Mitochondrial dna Kuntz, E. M., Baquero, P., Michie, A. M., Dunn, K., Tardito, S.,
mutations in cuban optic and peripheral neuropathy. Journal of Holyoake, T. L., Helgason, G. V., & Gottlieb, E. (2017). Targeting
Neuro‐Ophthalmology, 14, 135–140. https://doi.org/10.1097/ mitochondrial oxidative phosphorylation eradicates therapy‐
00041327-199409000-00003 resistant chronic myeloid leukemia stem cells. Nature Medicine, 23,
Jonckheere, A. I., Smeitink, J. A. M., & Rodenburg, R. J. T. (2012). 1234–1240. https://doi.org/10.1038/nm.4399
Mitochondrial ATP synthase: Architecture, function and pathology. Lagadinou, E. D., Sach, A., Callahan, K., Rossi, R. M., Neering, S. J.,
Journal of Inherited Metabolic Disease, 35(2), 211–225. https://doi. Minhajuddin, M., Ashton, J. M., Pei, S., Grose, V., O'Dwyer, K. M.,
org/10.1007/s10545-011-9382-9 Liesveld, J. L., Brookes, P. S., Becker, M. W., & Jordan, C. T. (2013).
Jones, R. A., Robinson, T. J., Liu, J. C., Shrestha, M., Voisin, V., Ju, Y., BCL‐2 inhibition targets oxidative phosphorylation and selectively
Chung, P. E. D., Pellecchia, G., Fell, V. L., Bae, S., Muthuswamy, L., eradicates quiescent human leukemia stem cells. Cell Stem Cell, 12,
Datti, A., Egan, S. E., Jiang, Z., Leone, G., Bader, G. D., Schimmer, A., 329–341. https://doi.org/10.1016/j.stem.2012.12.013
Lapuente‐Brun, E., Moreno‐Loshuertos, R., Aciń‐Pérez, R., Latorre‐ with Leigh syndrome. American Journal of Human Genetics, 63,
Pellicer, A., Colaś, C., Balsa, E., Perales‐Clemente, E., Quirós, P. M., 1598–1608. https://doi.org/10.1086/302154
Calvo, E., Rodríguez‐Hernández, M. A., Navas, P., Cruz, R., Lonardo, E., Cioffi, M., Sancho, P., Sanchez‐Ripoll, Y., Trabulo, S. M.,
Carracedo, Á., Loṕez‐Otín, C., Peŕez‐Martos, A., Fernańdez‐Silva, P., Dorado, J., Balic, A., Hidalgo, M., & Heeschen, C. (2013). Metformin
Fernańdez‐Vizarra, E., & Enríquez, J. A. (2013). Supercomplex targets the metabolic achilles heel of human pancreatic cancer stem
assembly determines electron flux in the mitochondrial electron cells. PLoS One, 8, 76518. https://doi.org/10.1371/journal.pone.
transport chain. Science, 340, 1567–1570. https://doi.org/10.1126/ 0076518
science.1230381 De Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A.,
Laugel, V., This‐Bernd, V., Cormier‐Daire, V., Speeg‐Schatz, C., de Saint‐ Taanman, J. W., Benayoun, E., Chrétien, D., Kadhom, N., Lombès, A.,
Martin, A., & Fischbach, M. (2007). Early‐onset ophthalmoplegia in De Baulny, H. O., Niaudet, P., Munnich, A., Rustin, P., & Rötig, A.
Leigh‐like syndrome due to NDUFV1 mutations. Pediatric Neurology, (2001). A mutant mitochondrial respiratory chain assembly protein
36, 54–57. https://doi.org/10.1016/j.pediatrneurol.2006.08.007 causes complex III deficiency in patients with tubulopathy, en-
Lazarou, M., Thorburn, D. R., Ryan, M. T., & McKenzie, M. (2009). cephalopathy and liver failure. Nature Genetics, 29, 57–60. https://
Assembly of mitochondrial complex I and defects in disease. doi.org/10.1038/ng706
Biochimica et Biophysica Acta—Molecular Cell Research, 1793, Lopez‐Fabuel, I., Le Douce, J., Logan, A., James, A. M., Bonvento, G.,
78–88. https://doi.org/10.1016/j.bbamcr.2008.04.015 Murphy, M. P., Almeida, A., & Bolaños, J. P. (2016). Complex I
Leary, S. C., Kaufman, B. A., Pellecchia, G., Guercin, G. H., Mattman, A., assembly into supercomplexes determines differential mitochondrial
Jaksch, M., & Shoubridge, E. A. (2004). Human SCO1 and SCO2 have ROS production in neurons and astrocytes. Proceedings of the
independent, cooperative functions in copper delivery to cyto- National Academy of Sciences of the United States of America, 113(46),
chrome c oxidase. Human Molecular Genetics, 13, 1839–1848. 13063–13068. https://doi.org/10.1073/pnas.1613701113
https://doi.org/10.1093/hmg/ddh197 Luberichs, J., Leo‐Kottler, B., Besch, D., & Fauser, S. (2002). A mutational
Legros, F., Chatzoglou, E., Frachon, P., Ogier De Baulny, H., Laforêt, P., hot spot in the mithochondrial ND6 gene in patients with Leber's
Jardel, C., Godinot, C., & Lombès, A. (2001). Functional characteri- hereditary optic neuropathy. Graefe's Archive for Clinical and
zation of novel mutations in the human cytochrome b gene. Experimental Ophthalmology, 240, 96–100. https://doi.org/10.
European Journal of Human Genetics, 9, 510–518. https://doi.org/ 1007/s00417-001-0423-1
10.1038/sj.ejhg.5200678 Ma, Y. Y., Wu, T. F., Liu, Y. P., Wang, Q., Li, X. Y., Ding, Y., Song, J. Q.,
Lenaz, G., Fato, R., Genova, M. L., Bergamini, C., Bianchi, C., & Biondi, A. Shi, X. Y., Zhang, W. N., Zhao, M., Hu, L. Y., Ju, J., Wang, Z. L.,
(2006). Mitochondrial complex I: Structural and functional aspects. Yang, Y. L., & Zou, L. P. (2014). Two compound frame‐shift
Biochimica et Biophysica Acta—Bioenergetics, 1757, 1406–1420. mutations in succinate dehydrogenase gene of a Chinese boy with
https://doi.org/10.1016/j.bbabio.2006.05.007 encephalopathy. Brain and Development, 36, 394–398. https://doi.
Letts, J. A., Fiedorczuk, K., & Sazanov, L. A. (2016). The architecture of org/10.1016/j.braindev.2013.06.003
respiratory supercomplexes. Nature, 537, 644–648. https://doi.org/ Maitra, A., Cohen, Y., Gillespie, S. E. D., Mambo, E., Fukushima, N.,
10.1038/nature19774 Hoque, M. O., Shah, N., Goggins, M., Califano, J., Sidransky, D., &
Letts, J. A., & Sazanov, L. A. (2017). Clarifying the supercomplex: The Chakravarti, A. (2004). The human MitoChip: A high‐throughput
higher‐order organization of the mitochondrial electron transport sequencing microarray for mitochondrial mutation detection.
chain. Nature Structural and Molecular Biology, 24, 800–808. https:// Genome Research, 14, 812–819. https://doi.org/10.1101/gr.
doi.org/10.1038/nsmb.3460 2228504
Li, L., & Li, W. (2015). Epithelial‐mesenchymal transition in human cancer: Makino, M., Horai, S., Goto, Y. I., & Nonaka, I. (1998). Confirmation that a
Comprehensive reprogramming of metabolism, epigenetics, and T‐to‐C mutation at 9176 in mitochondrial DNA is an additional
differentiation. Pharmacology and Therapeutics, 150, 33–46. candidate mutation for Leigh's syndrome. Neuromuscular Disorders,
https://doi.org/10.1016/j.pharmthera.2015.01.004 8, 149–151. https://doi.org/10.1016/S0960-8966(98)00017-0
Li, L. D., Sun, H. F., Liu, X. X., Gao, S. P., Jiang, H. L., Hu, X., & Jin, W. Maklashina, E., Berthold, D. A., & Cecchini, G. (1998). Anaerobic
(2015). Down‐regulation of NDUFB9 promotes breast cancer cell expression of Escherichia coli succinate dehydrogenase: Functional
proliferation, metastasis by mediating mitochondrial metabolism. replacement of fumarate reductase in the respiratory chain during
PLoS One, 10(12), e0144441. https://doi.org/10.1371/journal.pone. anaerobic growth. Journal of Bacteriology, 180, 5989–5996. https://
0144441 doi.org/10.1128/jb.180.22.5989-5996.1998
Lightowlers, R. N., Chrzanowska‐Lightowlers, Z. M., & Russell, O. M. Malfatti, E., Bugiani, M., Invernizzi, F., De Souza, C. F. M., Farina, L.,
(2020). Mitochondrial transplantation—A possible therapeutic for Carrara, F., Lamantea, E., Antozzi, C., Confalonieri, P.,
mitochondrial dysfunction? EMBO Reports, 21, 50964. https://doi. Sanseverino, M. T., Giugliani, R., Uziel, G., & Zeviani, M. (2007).
org/10.15252/embr.202050964 Novel mutations of ND genes in complex I deficiency associated
Lim, S. C., Hroudová, J., Van Bergen, N. J., Lopez Sanchez, M. I. G., with mitochondrial encephalopathy. Brain, 130, 1894–1904. https://
Trounce, I. A., & McKenzie, M. (2016). Loss of mitochondrial DNA‐ doi.org/10.1093/brain/awm114
encoded protein ND1 results in disruption of complex I biogenesis Mancuso, M., Filosto, M., Stevens, J. C., Patterson, M., Shanske, S.,
during early stages of assembly. The FASEB Journal, 30, 2236–2248. Krishna, S., & DiMauro, S. (2003). Mitochondrial myopathy and
https://doi.org/10.1096/fj.201500137R complex III deficiency in a patient with a new stop‐codon mutation
Liutkeviciene, R., Sidaraite, A., Kuliaviene, L., Glebauskiene, B., Jurkute, N., (G339X) in the cytochrome b gene. Journal of the Neurological
Aluzaite‐Baranauskiene, L., Gelzinis, A., & Zemaitiene, R. (2021). A Sciences, 209, 61–63. https://doi.org/10.1016/S0022-510X(02)
typical case presentation with spontaneous visual recovery in 00462-8
patient diagnosed with leber hereditary optic neuropathy due to Maranzana, E., Barbero, G., Falasca, A. I., Lenaz, G., & Genova, M. L.
rare point mutation in mt‐nd4 gene (M.11253t>c) and literature (2013). Mitochondrial respiratory supercomplex association limits
review. Medicina (Lithuania), 57(3), 202. https://doi.org/10.3390/ production of reactive oxygen species from complex I. Antioxidants
medicina57030202 and Redox Signaling, 19, 1469–1480. https://doi.org/10.1089/ars.
Loeffen, J., Smeitink, J. A. M., Triepels, R., Smeets, R., Schuelke, M., 2012.4845
Sengers, R., Trijbels, F., Hamel, B., Mullaart, R., & Van Heuvel, L. D. Marquis, J., Lefebvre, G., Kourmpetis, Y. A. I., Kassam, M., Ronga, F.,
(1998). The first nuclear‐encoded complex I mutation in a patient De Marchi, U., Wiederkehr, A., & Descombes, P. (2017). MitoRS, a
method for high throughput, sensitive, and accurate detection of Mirzazadeh, M., & Poulton, J. (2017). Use of FGF‐21 as a biomarker
mitochondrial DNA heteroplasmy. BMC Genomics, 18, 326. https:// of mitochondrial disease in clinical practice. Journal of Clinical
doi.org/10.1186/s12864-017-3695-5 Medicine, 6, 80. https://doi.org/10.3390/jcm6080080
Mathiesen, C., & Hägerhäll, C. (2002). Transmembrane topology of the Moslemi, A. R., Darin, N., Tulinius, M., Oldfors, A., & Holme, E. (2005). Two
NuoL, M and N subunits of NADH:quinone oxidoreductase and their new mutations in the MTATP6 gene associated with Leigh
homologues among membrane‐bound hydrogenases and bona fide syndrome. Neuropediatrics, 36, 314–318. https://doi.org/10.1055/
antiporters. Biochimica et Biophysica Acta—Bioenergetics, 1556, s-2005-872845
121–132. https://doi.org/10.1016/S0005-2728(02)00343-2 Moslemi, A. R., Darin, N., Tulinius, M., Wiklund, L. M., Holme, E., &
Mathupala, S. P., Ko, Y. H., & Pedersen, P. L. (2010). The pivotal roles of Oldfors, A. (2008). Progressive encephalopathy and complex I
mitochondria in cancer: Warburg and beyond and encouraging deficiency associated with mutations in MTND1. Neuropediatrics, 39,
prospects for effective therapies. Biochimica et Biophysica Acta— 24–28. https://doi.org/10.1055/s-2008-1076739
Bioenergetics, 1797, 1225–1230. https://doi.org/10.1016/j.bbabio. Munakata, K., Tanaka, M., Mori, K., Washizuka, S., Yoneda, M., Tajima, O.,
2010.03.025 Akiyama, T., Nanko, S., Kunugi, H., Tadokoro, K., Ozaki, N., Inada, T.,
Matsumoto, M., Hayasaka, S., Kadoi, C., Hotta, Y., Fujiki, K., Fujimaki, T., Sakamoto, K., Fukunaga, T., Iijima, Y., Iwata, N., Tatsumi, M.,
Takeda, M., Ishida, N., Endo, S., & Kanai, A. (1999). Secondary Yamada, K., Yoshikawa, T., & Kato, T. (2004). Mitochondrial DNA
mutations of mitochondrial DNA in Japanese patients with Leber's 3644T→C mutation associated with bipolar disorder. Genomics, 84,
hereditary optic neuropathy. Ophthalmic Genetics, 20, 153–160. 1041–1050. https://doi.org/10.1016/j.ygeno.2004.08.015
https://doi.org/10.1076/opge.20.3.153.2281 Naess, K., Freyer, C., Bruhn, H., Wibom, R., Malm, G., Nennesmo, I.,
Matsuno‐Yagi, A., & Hatefi, Y. (1999). Ubiquinol:cytochrome c oxido- von Döbeln, U., & Larsson, N. G. (2009). MtDNA mutations are a
reductase: Effects of inhibitors on reverse electron transfer from the common cause of severe disease phenotypes in children with Leigh
iron‐sulfur protein to cytochrome b. Journal of Biological Chemistry, syndrome. Biochimica et Biophysica Acta—Bioenergetics, 1787,
274, 9283–9288. https://doi.org/10.1074/jbc.274.14.9283 484–490. https://doi.org/10.1016/j.bbabio.2008.11.014
Mayorov, V., Biousse, V., Newman, N. J., & Brown, M. D. (2005). The role Neupert, W., & Herrmann, J. M. (2007). Translocation of proteins into
of the ND5 gene in LHON: Characterization of a new, heteroplasmic mitochondria. Annual Review of Biochemistry, 76, 723–749. https://
LHON mutation. Annals of Neurology, 58, 807–811. https://doi.org/ doi.org/10.1146/annurev.biochem.76.052705.163409
10.1002/ana.20669 Ngu, L. H., Nijtmans, L. G., Distelmaier, F., Venselaar, H., van Emst‐de
McFarland, R., Kirby, D. M., Fowler, K. J., Ohtake, A., Ryan, M. T., Vries, S. E., van den Brand, M. A. M., Stoltenborg, B. J. M.,
Amor, D. J., Fletcher, J. M., Dixon, J. W., Collins, F. A., Wintjes, L. T., Willems, P. H., van den Heuvel, L. P., Smeitink, J. A., &
Turnbull, D. M., Taylor, R. W., & Thorburn, D. R. (2004). De novo Rodenburg, R. J. T. (2012). A catalytic defect in mitochondrial
mutations in the mitochondrial ND3 gene as a cause of infantile respiratory chain complex I due to a mutation in NDUFS2 in a
mitochondrial encephalopathy and complex I deficiency. Annals of patient with Leigh syndrome. Biochimica et Biophysica Acta—
Neurology, 55, 58–64. https://doi.org/10.1002/ana.10787 Molecular Basis of Disease, 1822, 168–175. https://doi.org/10.
De Meirleir, L., Seneca, S., Lissens, W., Schoentjes, E., & Desprechins, B. 1016/j.bbadis.2011.10.012
(1995). Bilateral striatal necrosis with a novel point mutation in the Nijtmans, L. G. J., Henderson, N. S., Attardi, G., & Holt, I. J. (2001).
mitochondrial ATPase 6 gene. Pediatric Neurology, 13(3), 242–246. Impaired ATP synthase assembly associated with a mutation in the
https://doi.org/10.1016/0887-8994(95)00184-H human ATP synthase subunit 6 gene. Journal of Biological Chemistry,
Mimaki, M., Ikota, A., Sato, A., Komaki, H., Akanuma, J., Nonaka, I., & 276, 6755–6762. https://doi.org/10.1074/jbc.M008114200
Goto, Y. ichi (2003). A double mutation (G11778A and G12192A) in Nobrega, F. G., Nobrega, M. P., & Tzagoloff, A. (1992). BCS1, a novel gene
mitochondrial DNA associated with Leber's hereditary optic neu- required for the expression of functional Rieske iron‐sulfur protein
ropathy and cardiomyopathy. Journal of Human Genetics, 48, 47–50. in Saccharomyces cerevisiae. The EMBO Journal, 11, 3821–3829.
https://doi.org/10.1007/s100380300005 https://doi.org/10.1002/j.1460-2075.1992.tb05474.x
Mitchell, A. L., Elson, J. L., Howell, N., Taylor, R. W., & Turnbull, D. M. Nowinski, S. M., Solmonson, A., Rusin, S. F., Maschek, J. A., Bensard, C. L.,
(2006). Sequence variation in mitochondrial complex I genes: Fogarty, S., Jeong, M. Y., Lettlova, S., Berg, J. A., Morgan, J. T.,
Mutation or polymorphism. Journal of Medical Genetics, 43(2), Ouyang, Y., Naylor, B. C., Paulo, J. A., Funai, K., Cox, J. E., Gygi, S. P.,
175–179. https://doi.org/10.1136/jmg.2005.032474 Winge, D. R., Deberardinis, R. J., & Rutter, J. (2020). Mitochondrial
Moraes, C. T., DiMauro, S., Zeviani, M., Lombes, A., Shanske, S., fatty acid synthesis coordinates oxidative metabolism in mammalian
Miranda, A. F., Nakase, H., Bonilla, E., Werneck, L. C., Servidei, S., mitochondria. eLife, 9, e58041. https://doi.org/10.7554/ELIFE.
Nonaka, I., Koga, Y., Spiro, A. J., W. Brownell, A. K., Schmidt, B., 58041
Schotland, D. L., Zupanc, M., DeVivo, D. C., Schon, E. A., & Opdal, S. H., Vege, Å., Egeland, T., Musse, M. A., & Rognum, T. O. (2002).
Rowland, L. P. (1989). Mitochondrial DNA deletions in progressive Possible role of mtDNA mutations in sudden infant death. Pediatric
external ophthalmoplegia and Kearns‐Sayre syndrome. New England Neurology, 27, 23–29. https://doi.org/10.1016/S0887-8994(02)
Journal of Medicine, 320, 1293–1299. https://doi.org/10.1056/ 00384-3
nejm198905183202001 Ostergaard, E., Rodenburg, R. J., van den Brand, M., Thomsen, L. L.,
Morán, M., Rivera, H., Sánchez‐Aragó, M., Blázquez, A., Merinero, B., Duno, M., Batbayli, M., Wibrand, F., & Nijtmans, L. (2011).
Ugalde, C., Arenas, J., Cuezva, J. M., & Martín, M. A. (2010). Respiratory chain complex I deficiency due to NDUFA12 mutations
Mitochondrial bioenergetics and dynamics interplay in complex I‐ as a new cause of leigh syndrome. Journal of Medical Genetics, 48,
deficient fibroblasts. Biochimica et Biophysica Acta—Molecular Basis 737–740. https://doi.org/10.1136/jmg.2011.088856
of Disease, 1802, 443–453. https://doi.org/10.1016/j.bbadis.2010. Pagniez‐Mammeri, H., Landrieu, P., Legrand, A., & Slama, A. (2010).
02.001 Leukoencephalopathy with vanishing white matter caused by
Moreno‐Sánchez, R., Rodríguez‐Enríquez, S., Marín‐Hernández, A., & compound heterozygous mutations in mitochondrial complex I
Saavedra, E. (2007). Energy metabolism in tumor cells. FEBS Journal, NDUFS1 subunit. Molecular Genetics and Metabolism, 101,
274, 1393–1418. https://doi.org/10.1111/j.1742-4658.2007. 297–298. https://doi.org/10.1016/j.ymgme.2010.07.005
05686.x Pecina, P., Nůsková, H., Karbanová, V., Kaplanová, V., Mráček, T., &
Morovat, A., Weerasinghe, G., Nesbitt, V., Hofer, M., Agnew, T., Houštěk, J. (2018). Role of the mitochondrial ATP synthase central
Quaghebeur, G., Sergeant, K., Fratter, C., Guha, N., stalk subunits γ and δ in the activity and assembly of the mammalian
enzyme. Biochimica et Biophysica Acta—Bioenergetics, 1859, variation across human cancers. eLife, 5, e10769. https://doi.org/10.
374–381. https://doi.org/10.1016/j.bbabio.2018.02.007 7554/eLife.10769
Peng, Q., Zhou, Q., Zhou, J., Zhong, D., Pan, F., & Liang, H. (2008). Stable Rich, P. R. (2003). The molecular machinery of Keilin's respiratory chain.
RNA interference of hexokinase II gene inhibits human colon cancer Biochemical Society Transactions, 31, 1095–1105. https://doi.org/10.
LoVo cell growth in vitro and in vivo. Cancer Biology and Therapy, 7, 1042/bst0311095
1128–1135. https://doi.org/10.4161/cbt.7.7.6199 Rizzuto, R., De Stefani, D., Raffaello, A., & Mammucari, C. (2012).
Petros, J. A., Baumann, A. K., Ruiz‐Pesini, E., Amin, M. B., Sun, C. Q., Mitochondria as sensors and regulators of calcium signalling. Nature
Hall, J., Lim, S. D., Issa, M. M., Flanders, W. D., Hosseini, S. H., Reviews Molecular Cell Biology, 13, 566–578. https://doi.org/10.
Marshall, F. F., & Wallace, D. C. (2005). MtDNA mutations increase 1038/nrm3412
tumorigenicity in prostate cancer. Proceedings of the National Rocha, H., Flores, C., Campos, Y., Arenas, J., Vilarinho, L., Santorelli, F. M.,
Academy of Sciences of the United States of America, 102(3), & Torroni, A. (1999). About the “pathological” role of the mtDNA
719–724. https://doi.org/10.1073/pnas.0408894102 T3308C mutation…. American Journal of Human Genetics, 65,
Petruzzella, V., Di Giacinto, G., Scacco, S., Piemonte, F., Torraco, A., 1457–1459. https://doi.org/10.1086/302641
Carrozzo, R., Vergari, R., Dionisi‐Vici, C., Longo, D., Tessa, A., Roos, S., Sofou, K., Hedberg‐Oldfors, C., Kollberg, G., Lindgren, U.,
Papa, S., & Bertini, E. (2003). Atypical Leigh syndrome associated Thomsen, C., Tulinius, M., & Oldfors, A. (2019). Mitochondrial
with the D393N mutation in the mitochondrial ND5 subunit. complex IV deficiency caused by a novel frameshift variant in MT‐
Neurology, 61, 1017–1018. https://doi.org/10.1212/01.WNL. CO2 associated with myopathy and perturbed acylcarnitine profile.
0000080363.10902.E9 European Journal of Human Genetics, 27, 331–335. https://doi.org/
Peverelli, L., Catania, A., Marchet, S., Ciasca, P., Cammarata, G., Melzi, L., 10.1038/s41431-018-0286-0
Bellino, A., Fancellu, R., Lamantea, E., Capristo, M., Caporali, L., Ruiter, E. M., Siers, M. H., van den Elzen, C., van Engelen, B. G.,
La Morsgia, C., Carelli, V., Ghezzi, D., Bianchi Marzoli, S., & Smeitink, J. A. M., Rodenburg, R. J., & Hol, F. A. (2007). The
Lamperti, C. (2021). Leber's hereditary optic neuropathy: A report mitochondrial 13513G>A mutation is most frequent in Leigh
on novel mtDNA pathogenic variants. Frontiers in Neurology, 12, syndrome combined with reduced complex I activity, optic atrophy
657317. https://doi.org/10.3389/fneur.2021.657317 and/or Wolff‐Parkinson‐White. European Journal of Human Genetics,
Pfeiffer, K., Gohil, V., Stuart, R. A., Hunte, C., Brandt, U., Greenberg, M. L., & 15, 155–1561. https://doi.org/10.1038/sj.ejhg.5201735
Schägger, H. (2003). Cardiolipin stabilizes respiratory chain super- Saada, A., Edvardson, S., Rapoport, M., Shaag, A., Amry, K., Miller, C.,
complexes. Journal of Biological Chemistry, 278, 52873–52880. https:// Lorberboum‐Galski, H., & Elpeleg, O. (2008). C6ORF66 is an
doi.org/10.1074/jbc.M308366200 assembly factor of mitochondrial complex I. American Journal of
Potluri, P., Davila, A., Ruiz‐Pesini, E., Mishmar, D., O'Hearn, S., Hancock, S., Human Genetics, 82, 32–38. https://doi.org/10.1016/j.ajhg.2007.
Simon, M., Scheffler, I. E., Wallace, D. C., & Procaccio, V. (2009). A novel 08.003
NDUFA1 mutation leads to a progressive mitochondrial complex I‐ Sacconi, S., Salviati, L., Sue, C. M., Shanske, S., Davidson, M. M., Bonilla, E.,
specific neurodegenerative disease. Molecular Genetics and Metabolism, Naini, A. B., De Vivo, D. C., & DiMauro, S. (2003). Mutation screening
96, 189–195. https://doi.org/10.1016/j.ymgme.2008.12.004 in patients with isolated cytochrome c oxidase deficiency. Pediatric
Procaccio, V., & Wallace, D. C. (2004). Late‐onset Leigh syndrome in a Research, 53(2), 224–230. https://doi.org/10.1203/00006450-
patient with mitochondrial complex I NDUFS8 mutations. Neurology, 200302000-00005
62, 1899–1901. https://doi.org/10.1212/01.WNL.0000125251. Sánchez, E., Lobo, T., Fox, J. L., Zeviani, M., Winge, D. R., & Fernández‐
56131.65 Vizarra, E. (2013). LYRM7/MZM1L is a UQCRFS1 chaperone
Putignani, L., Raffa, S., Pescosolido, R., Rizza, T., Del Chierico, F., Leone, L., involved in the last steps of mitochondrial complex III assembly in
Aimati, L., Signore, F., Carrozzo, R., Callea, F., Torrisi, M. R., & human cells. Biochimica et Biophysica Acta—Bioenergetics, 1827,
Grammatico, P. (2012). Preliminary evidences on mitochondrial 285–293. https://doi.org/10.1016/j.bbabio.2012.11.003
injury and impaired oxidative metabolism in breast cancer. Santidrian, A. F., Matsuno‐Yagi, A., Ritland, M., Seo, B. B., LeBoeuf, S. E.,
Mitochondrion, 12, 363–369. https://doi.org/10.1016/j.mito.2012. Gay, L. J., Yagi, T., & Felding‐Habermann, B. (2013). Mitochondrial
02.003 complex I activity and NAD+/NADH balance regulate breast cancer
Rahman, S., Taanman, J. W., Cooper, J. M., Nelson, I., Hargreaves, I., progression. Journal of Clinical Investigation, 123, 1068–1081.
Meunier, B., Hanna, M. G., García, J. J., Capaldi, R. A., Lake, B. D., https://doi.org/10.1172/JCI64264
Leonard, J. V., & Schapira, A. H. V. (1999). A missense mutation of Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C., & DiMauro, S.
cytochrome oxidase subunit II causes defective assembly and (1993). The mutation at nt 8993 of mitochondrial DNA is a common
myopathy. American Journal of Human Genetics, 65, 1030–1039. cause of Leigh's syndrome. Annals of Neurology, 34, 827–834.
https://doi.org/10.1086/302590 https://doi.org/10.1002/ana.410340612
Rednam, S. P., Erez, A., Druker, H., Janeway, K. A., Kamihara, J., Saraste, M. (1999). Oxidative phosphorylation at the fin de siecle. Science,
Kohlmann, W. K., Nathanson, K. L., States, L. J., Tomlinson, G. E., 283, 1488–1493. https://doi.org/10.1126/science.283.5407.1488
Villani, A., Voss, S. D., Schiffman, J. D., & Wasserman, J. D. (2017). Sarzi, E., Brown, M. D., Lebon, S., Chretien, D., Munnich, A., Rotig, A., &
Von Hippel‐Lindau and hereditary pheochromocytoma/paraganglio- Procaccio, V. (2007). A novel recurrent mitochondrial DNA mutation
ma syndromes: Clinical features, genetics, and surveillance recom- in ND3 gene is associated with isolated complex I deficiency causing
mendations in childhood. Clinical Cancer Research, 23, e68–e75. leigh syndrome and dystonia. American Journal of Medical Genetics,
https://doi.org/10.1158/1078-0432.CCR-17-0547 Part A, 143A, 33–41. https://doi.org/10.1002/ajmg.a.31565
Renkema, G. H., Wortmann, S. B., Smeets, R. J., Venselaar, H., Antoine, M., Saxena, N., Maio, N., Crooks, D. R., Ricketts, C. J., Yang, Y., Wei, M. H.,
Visser, G., Ben‐Omran, T., Van Den Heuvel, L. P., Timmers, H. J., Fan, T. W. M., Lane, A. N., Sourbier, C., Singh, A., Killian, J. K.,
Smeitink, J. A., & Rodenburg, R. J. T. (2015). SDHA mutations Meltzer, P. S., Vocke, C. D., Rouault, T. A., & Linehan, W. M. (2016).
causing a multisystem mitochondrial disease: Novel mutations and SDHB‐deficient cancers: The role of mutations that impair iron sulfur
genetic overlap with hereditary tumors. European Journal of Human cluster delivery. Journal of the National Cancer Institute, 108, djv287.
Genetics, 23, 202–209. https://doi.org/10.1038/ejhg.2014.80 https://doi.org/10.1093/jnci/djv287
Reznik, E., Miller, M. L., Şenbabaoğlu, Y., Riaz, N., Sarungbam, J., Sazanov, L. A., & Hinchliffe, P. (2006). Structure of the hydrophilic domain
Tickoo, S. K., Al‐Ahmadie, H. A., Lee, W., Seshan, V. E., of respiratory complex I from Thermus thermophilus. Science, 311,
Hakimi, A. A., & Sander, C. (2016). Mitochondrial DNA copy number 1430–1436. https://doi.org/10.1126/science.1123809
Schägger, H., Link, T. A., Engel, W. D., & von Jagow, G. (1986). Isolation of Dixon, J., & Wallace, D. C. (1995). Leber's hereditary optic
the eleven protein subunits of the bc1 complex from beef heart. neuropathy plus dystonia is caused by a mitochondrial DNA point
Methods in Enzymology, 126, 224–237. https://doi.org/10.1016/ mutation. Annals of Neurology, 38, 163–169. https://doi.org/10.
S0076-6879(86)26024-3. 1002/ana.410380207
Schägger, H., & Pfeiffer, K. (2000). Supercomplexes in the respiratory Sica, V., Bravo‐San Pedro, J. M., Stoll, G., & Kroemer, G. (2020). Oxidative
chains of yeast and mammalian mitochondria. The EMBO Journal, 19, phosphorylation as a potential therapeutic target for cancer therapy.
1777–1783. https://doi.org/10.1093/emboj/19.8.1777 International Journal of Cancer, 146, 10–17. https://doi.org/10.
Schägger, H., & Pfeiffer, K. (2001). The ratio of oxidative phosphorylation 1002/ijc.32616
complexes I‐V in bovine heart mitochondria and the composition of Simonnet, H., Alazard, N., Pfeiffer, K., Gallou, C., Béroud, C., Demont, J.,
respiratory chain supercomplexes. Journal of Biological Chemistry, Bouvier, R., Schägger, H., & Godinot, C. (2002). Low mitochondrial
276, 37861–37867. https://doi.org/10.1074/jbc.M106474200 respiratory chain content correlates with tumor aggressiveness in
Schon, E. A., Santra, S., Pallotti, F., & Girvin, M. E. (2001). Pathogenesis of renal cell carcinoma. Carcinogenesis, 23, 759–768. https://doi.org/
primary defects in mitochondrial ATP synthesis. Seminars in Cell and 10.1093/carcin/23.5.759
Developmental Biology, 12, 441–448. https://doi.org/10.1006/scdb. Spinelli, J. B., & Haigis, M. C. (2018). The multifaceted contributions of
2001.0281 mitochondria to cellular metabolism. Nature Cell Biology, 20,
Schöpf, B., Weissensteiner, H., Schäfer, G., Fazzini, F., Charoentong, P., 745–754. https://doi.org/10.1038/s41556-018-0124-1
Naschberger, A., Rupp, B., Fendt, L., Bukur, V., Giese, I., Sorn, P., Stefano, G. B., & Kream, R. M. (2016). Mitochondrial DNA heteroplasmy in
Sant'Anna‐Silva, A. C., Iglesias‐Gonzalez, J., Sahin, U., Kronenberg, F., human health and disease (review). Biomedical Reports, 4, 259–262.
Gnaiger, E., & Klocker, H. (2020). OXPHOS remodeling in high‐grade https://doi.org/10.3892/br.2016.590
prostate cancer involves mtDNA mutations and increased succinate Stewart, J. B., & Chinnery, P. F. (2015). The dynamics of mitochondrial
oxidation. Nature Communications, 11, 1487. https://doi.org/10. DNA heteroplasmy: Implications for human health and disease.
1038/s41467-020-15237-5 Nature Reviews Genetics, 16, 530–542. https://doi.org/10.1038/
Schubert, A. D., Channah Broner, E., Agrawal, N., London, N., Pearson, A., nrg3966
Gupta, A., Wali, N., Seiwert, T. Y., Wheelan, S., Lingen, M., Stojanovski, D., Johnston, A. J., Streimann, I., Hoogenrad, N. J., &
Macleod, K., Allen, H., Chatterjee, A., Vassiliki, S., Gaykalova, D., Ryan, M. T. (2003). Import of nuclear‐encoded proteins into
Hoque, M. O., Sidransky, D., Suresh, K., & Izumchenko, E. (2020). mitochondria. Experimental Physiology, 88, 57–64. https://doi.org/
Somatic mitochondrial mutation discovery using ultra‐deep 10.1113/eph8802501
sequencing of the mitochondrial genome reveals spatial tumor Stroud, D. A., Surgenor, E. E., Formosa, L. E., Reljic, B., Frazier, A. E.,
heterogeneity in head and neck squamous cell carcinoma. Cancer Dibley, M. G., Osellame, L. D., Stait, T., Beilharz, T. H.,
Letters, 471, 49–60. https://doi.org/10.1016/j.canlet.2019.12.006 Thorburn, D. R., Salim, A., & Ryan, M. T. (2016). Accessory subunits
Schuelke, M., Smeitink, J., Mariman, E., Loeffen, J., Plecko, B., Trijbels, F., are integral for assembly and function of human mitochondrial
Stockler‐Ipsiroglu, S., & Van den Heuvel, L. (1999). Mutant NDUFV1 complex I. Nature, 538, 123–126. https://doi.org/10.1038/
subunit of mitochondrial complex I causes leukodystrophy and nature19754
myoclonic epilepsy. Nature Genetics, 21, 260–261. https://doi.org/ Sun, F., Huo, X., Zhai, Y., Wang, A., Xu, J., Su, D., Bartlam, M., & Rao, Z.
10.1038/6772 (2005). Crystal structure of mitochondrial respiratory membrane
Schuelke, M., Krude, H., Finckh, B., Mayatepek, E., Janssen, A., protein complex II. Cell, 121, 1043–1057. https://doi.org/10.1016/j.
Schmelz, M., Trefz, F., Trijbels, F., & Smeitink, J. (2002). Septo‐ cell.2005.05.025
optic dysplasia associated with a new mitochondrial cytochrome b Sun, J., & Trumpower, B. L. (2003). Superoxide anion generation by the
mutation. Annals of Neurology, 51, 388–392. https://doi.org/10. cytochrome bc1 complex. Archives of Biochemistry and Biophysics,
1002/ana.10151 419, 198–206. https://doi.org/10.1016/j.abb.2003.08.028
Set, K. K., Sen, K., Huq, A. H. M., & Agarwal, R. (2019). Mitochondrial Sun, W., Zhou, S., Chang, S. S., McFate, T., Verma, A., & Califano, J. A.
disorders of the nervous system: A review. Clinical Pediatrics, 58, (2009). Mitochondrial mutations contribute to HIFIα accumulation
381–394. https://doi.org/10.1177/0009922818821890 via increased reactive oxygen species and up‐regulated pyruvate
Shanske, S., Coku, J., Lu, J., Ganesh, J., Krishna, S., Tanji, K., Bonilla, E., dehydrogenease kinase 2 in head and neck squamous cell carcinoma.
Naini, A. B., Hirano, M., & DiMauro, S. (2008). The G13513A mutation Clinical Cancer Research, 15, 476–484. https://doi.org/10.1158/
in the ND5 gene of mitochondrial DNA as a common cause of MELAS 1078-0432.CCR-08-0930
or Leigh syndrome: Evidence from 12 cases. Archives of Neurology, 65, Sundaramurthy, S., SelvaKumar, A., Ching, J., Dharani, V., Sarangapani, S.,
368–372. https://doi.org/10.1001/archneurol.2007.67 & Yu‐Wai‐Man, P. (2021). Leber hereditary optic neuropathy—New
Sharma, L., Lu, J., & Bai, Y. (2009). Mitochondrial respiratory complex I: insights and old challenges. Graefe's Archive for Clinical and
Structure, function and implication in human diseases. Current Experimental Ophthalmology, 259, 2461–2472. https://doi.org/10.
Medicinal Chemistry, 16, 1266–1277. https://doi.org/10.2174/ 1007/s00417-020-04993-1
092986709787846578 Taanman, J. W. (1999). The mitochondrial genome: Structure, transcrip-
Shimada, S., Shinzawa‐Itoh, K., Baba, J., Aoe, S., Shimada, A., Yamashita, E., tion, translation and replication. Biochimica et Biophysica Acta—
Kang, J., Tateno, M., Yoshikawa, S., & Tsukihara, T. (2017). Complex Bioenergetics, 1410, 103–123. https://doi.org/10.1016/S0005-
structure of cytochrome c—Cytochrome c oxidase reveals a novel 2728(98)00161-3
protein–protein interaction mode. The EMBO Journal, 36, 291–300. Tan, A. S., Baty, J. W., Dong, L. F., Bezawork‐Geleta, A., Endaya, B.,
https://doi.org/10.15252/embj.201695021 Goodwin, J., Bajzikova, M., Kovarova, J., Peterka, M., Yan, B.,
Shinzawa‐Itoh, K., Shimomura, H., Yanagisawa, S., Shimada, S., Pesdar, E. A., Sobol, M., Filimonenko, A., Stuart, S., Vondrusova, M.,
Takahashi, R., Oosaki, M., Ogura, T., & Tsukihara, T. (2016). Kluckova, K., Sachaphibulkij, K., Rohlena, J., … Berridge, M. V. (2015).
Purification of active respiratory supercomplex from bovine heart Mitochondrial genome acquisition restores respiratory function and
mitochondria enables functional studies. Journal of Biological tumorigenic potential of cancer cells without mitochondrial DNA.
Chemistry, 291, 4178–4184. https://doi.org/10.1074/jbc.M115. Cell Metabolism, 21, 81–94. https://doi.org/10.1016/j.cmet.2014.
680553 12.003
Shoffner, J. M., Brown, M. D., Stugard, C., June, A. S., Pollock, S., Tang, Y., Schon, E. A., Wilichowski, E., Vazquez‐Memije, M. E.,
Haas, R. H., Kaufman, A., Koontz, D., Kim, Y., Graham, J. R., Smith, E., Davidson, E., & King, M. P. (2000). Rearrangements of human
mitochondrial DNA (mtDNA): New insights into the regulation of Gavazzi, G., Mascalchi, M., Salvi, F., & Carelli, V. (2021). The
mtDNA copy number and gene expression. Molecular Biology of the m.3890G>A/MT‐ND1 mtDNA rare pathogenic variant: Expanding
Cell, 11, 1471–85. https://doi.org/10.1091/mbc.11.4.1471 clinical and MRI phenotypes. Mitochondrion, 60, 142–149. https://
Tatuch, Y., & Robinson, B. H. (1993). The mitochondrial DNA mutation at doi.org/10.1016/j.mito.2021.08.007
8993 associated with NARP slows the rate of ATP synthesis in Vafai, S. B., & Mootha, V. K. (2012). Mitochondrial disorders as windows
isolated lymphoblast mitochondria. Biochemical and Biophysical into an ancient organelle. Nature, 491, 374–383. https://doi.org/10.
Research Communications, 192, 124–128. https://doi.org/10.1006/ 1038/nature11707
bbrc.1993.1390 Vander Heiden, M. G., & DeBerardinis, R. J. (2017). Understanding the
Temperley, R. J., Seneca, S. H., Tonska, K., Bartnik, E., Bindoff, L. A., intersections between metabolism and cancer biology. Cell, 168,
Lightowlers, R. N., & Chrzanowska‐Lightowlers, Z. M. A. (2003). 657–669. https://doi.org/10.1016/j.cell.2016.12.039
Investigation of a pathogenic mtDNA microdeletion reveals a Viale, A., Corti, D., & Draetta, G. F. (2015). Tumors and mitochondrial
translation‐dependent deadenylation decay pathway in human respiration: A neglected connection. Cancer Research, 75,
mitochondria. Human Molecular Genetics, 12, 2341–2348. https:// 3687–3691. https://doi.org/10.1158/0008-5472.CAN-15-0491
doi.org/10.1093/hmg/ddg238 Viale, A., Pettazzoni, P., Lyssiotis, C. A., Ying, H., Sánchez, N., Marchesini, M.,
Tiranti, V., Corona, P., Greco, M., Taanman, J. W., Carrara, F., Lamantea, E., Carugo, A., Green, T., Seth, S., Giuliani, V., Kost‐Alimova, M., Muller, F.,
Nijtmans, L., Uziel, G., & Zeviani, M. (2000). A novel frameshift Colla, S., Nezi, L., Genovese, G., Deem, A. K., Kapoor, A., Yao, W.,
mutation of the mtDNA COIII gene leads to impaired assembly of Brunetto, E., … Draetta, G. F. (2014). Oncogene ablation‐resistant
cytochrome c oxidase in a patient affected by Leigh‐like syndrome. pancreatic cancer cells depend on mitochondrial function. Nature, 514,
Human Molecular Genetics, 9, 2733–2742. https://doi.org/10.1093/ 628–632. https://doi.org/10.1038/nature13611
hmg/9.18.2733 Visapää, I., Fellman, V., Vesa, J., Dasvarma, A., Hutton, J. L., Kumar, V.,
Triepels, R. H., Van Den Heuvel, L. P., Loeffen, J. L. C. M., Buskens, C. A. F., Payne, G. S., Makarow, M., Van Coster, R., Taylor, R. W.,
Smeets, R. J. P., Rubio Gozalbo, M. E., Budde, S. M. S., Turnbull, D. M., Suomalainen, A., & Peltonen, L. (2002). GRACILE
Mariman, E. C., Wijburg, F. A., Barth, P. G., Trijbels, J. M. F., & syndrome, a lethal metabolic disorder with iron overload, is caused
Smeitink, J. A. M. (1999). Leigh syndrome associated with a mutation by a point mutation in BCS1L. American Journal of Human Genetics,
in the NDUFS7 (PSST) nuclear encoded subunit of complex I. Annals 71, 863–76. https://doi.org/10.1086/342773
of Neurology, 45(6), 787–790. https://doi.org/10.1002/1531- Vogel, R. O., Smeitink, J. A. M., & Nijtmans, L. G. J. (2007). Human
8249(199906)45:6%3C787::AID-ANA13%3E3.0.CO;2-6 mitochondrial complex I assembly: A dynamic and versatile
Tsukihara, T., Aoyama, H., Yamashita, E., Tomizaki, T., Yamaguchi, H., process. Biochimica et Biophysica Acta—Bioenergetics, 1767,
Shinzawa‐Itoh, K., Nakashima, R., Yaono, R., & Yoshikawa, S. (1996). 1215–1227. https://doi.org/10.1016/j.bbabio.2007.07.008
The whole structure of the 13‐subunit oxidized cytochrome c Volobueva, A., Grechko, A., Yet, S. F., Sobenin, I., & Orekhov, A. (2019).
oxidase at 2.8 Å. Science, 272, 1136–44. https://doi.org/10.1126/ Changes in mitochondrial genome associated with predisposition to
science.272.5265.1136 atherosclerosis and related disease. Biomolecules, 9(8), 377. https://
Tuppen, H. A. L., Hogan, V. E., He, L., Blakely, E. L., Worgan, L., Al‐Dosary, doi.org/10.3390/biom9080377
M., Saretzki, G., Alston, C. L., Morris, A. A., Clarke, M., Jones, S., Vyas, S., Zaganjor, E., & Haigis, M. C. (2016). Mitochondria and cancer.
Devlin, A. M., Mansour, S., Chrzanowska‐Lightowlers, Z. M. A., Cell, 166, 555–566. https://doi.org/10.1016/j.cell.2016.07.002
Thorburn, D. R., McFarland, R., & Taylor, R. W. (2010). The p.M292T Wang, Y., Xia, Y., & Lu, Z. (2018). Metabolic features of cancer cells.
NDUFS2 mutation causes complex I‐deficient Leigh syndrome in Cancer Communications, 38, 65. https://doi.org/10.1186/s40880-
multiple families. Brain, 133, 2952–2963. https://doi.org/10.1093/ 018-0335-7
brain/awq232 Watt, I. N., Montgomery, M. G., Runswick, M. J., Leslie, A. G. W., &
Uehara, N., Mori, M., Tokuzawa, Y., Mizuno, Y., Tamaru, S., Kohda, M., Walker, J. E. (2010). Bioenergetic cost of making an adenosine
Moriyama, Y., Nakachi, Y., Matoba, N., Sakai, T., Yamazaki, T., triphosphate molecule in animal mitochondria. Proceedings of the
Harashima, H., Murayama, K., Hattori, K., Hayashi, J., Yamagata, T., National Academy of Sciences of the United States of America, 107(39),
Fujita, Y., Ito, M., Tanaka, M., … Okazaki, Y. (2014). New MT‐ND6 16823–16827. https://doi.org/10.1073/pnas.1011099107
and NDUFA1 mutations in mitochondrial respiratory chain dis- Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J.,
orders. Annals of Clinical and Translational Neurology, 1, 361–369. Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R. S., &
https://doi.org/10.1002/acn3.59 Chandel, N. S. (2010). Mitochondrial metabolism and ROS genera-
Ugalde, C., Janssen, R. J. R. J., van den Heuvel, L. P., Smeitink, J. A. M., & tion are essential for Kras‐mediated tumorigenicity. Proceedings of
Nijtmans, L. G. J. (2004). Differences in assembly or stability of the National Academy of Sciences of the United States of America,
complex I and other mitochondrial OXPHOS complexes in inherited 107(19), 8788–8793. https://doi.org/10.1073/pnas.1003428107
complex I deficiency. Human Molecular Genetics, 13, 659–667. Weinberg, S. E., & Chandel, N. S. (2015). Targeting mitochondria
https://doi.org/10.1093/hmg/ddh071 metabolism for cancer therapy. Nature Chemical Biology, 11, 9–15.
Ugalde, C., Hinttala, R., Timal, S., Smeets, R., Rodenburg, R. J. T., https://doi.org/10.1038/nchembio.1712
Uusimaa, J., van Heuvel, L. P., Nijtmans, L. G. J., Majamaa, K., & Weinberg, S. E., Singer, B. D., Steinert, E. M., Martinez, C. A.,
Smeitink, J. A. M. (2007). Mutated ND2 impairs mitochondrial Mehta, M. M., Martínez‐Reyes, I., Gao, P., Helmin, K. A., Abdala‐
complex I assembly and leads to Leigh syndrome. Molecular Genetics Valencia, H., Sena, L. A., Schumacker, P. T., Turka, L. A., &
and Metabolism, 90, 10–14. https://doi.org/10.1016/j.ymgme.2006. Chandel, N. S. (2019). Mitochondrial complex III is essential for
08.003 suppressive function of regulatory T cells. Nature, 565, 495–499.
Uusimaa, J., Finnilä, S., Vainionpää, L., Kärppä, M., Herva, R., Rantala, H., https://doi.org/10.1038/s41586-018-0846-z
Hassinen, I. E., & Majamaa, K. (2003). A mutation in mitochondrial Whitaker‐Menezes, D., Martinez‐Outschoorn, U. E., Flomenberg, N.,
DNA‐encoded cytochrome c oxidase II gene in a child with Alpers‐ Birbe, R. C., Witkiewicz, A. K., Howell, A., Pavlides, S., Tsirigos, A.,
Huttenlocher‐like disease. Pediatrics, 111, 262–268. https://doi.org/ Ertel, A., Pestell, R. G., Broda, P., Minetti, C., Lisanti, M. P., &
10.1542/peds.111.3.e262 Sotgia, F. (2011). Hyperactivation of oxidative mitochondrial
Vacchiano, V., Caporali, L., La Morgia, C., Carbonelli, M., Amore, G., metabolism in epithelial cancer cells in situ: Visualizing the
Bartolomei, I., Cascavilla, M. L., Barboni, P., Lamperti, C., Catania, A., therapeutic effects of metformin in tumor tissue. Cell Cycle, 10,
Chan, J. W., Karanja, R., Sadun, A. A., Liguori, R., Bianchi, A., 4047–4064. https://doi.org/10.4161/cc.10.23.18151
Wikstrom, M. K. F. (1977). Proton pump coupled to cytochrome c oxidase carcinoma. Molecular Medicine Reports, 11(6), 4496–4500. https://
in mitochondria. Nature, 266, 271–273. https://doi.org/10.1038/ doi.org/10.3892/mmr.2015.3240
266271a0 Yuan, Y., Wang, W., Li, H., Yu, Y., Tao, J., Huang, S., & Zeng, Z. (2015).
Wilfert, A. B., Sulovari, A., Turner, T. N., Coe, B. P., & Eichler, E. E. (2017). Nonsense and missense mutation of mitochondrial ND6 gene
Recurrent de novo mutations in neurodevelopmental disorders: promotes cell migration and invasion in human lung adenocarci-
Properties and clinical implications. Genome Medicine, 9, 101. noma. BMC Cancer, 15, 346. https://doi.org/10.1186/s12885-015-
https://doi.org/10.1186/s13073-017-0498-x 1349-z
Wissinger, B., Besch, D., Baumann, B., Fauser, S., Christ‐Adler, M., Yu‐Wai‐Man, P., Newman, N. J., Carelli, V., La Morgia, C., Biousse, V.,
Jurklies, B., Zrenner, E., & Leo‐Kottler, B. (1997). Mutation analysis Bandello, F. M., Clermont, C. V., Campillo, L. C., Leruez, S.,
of the ND6 gene in patients with lebers hereditary optic neuropathy. Moster, M. L., Cestari, D. M., Foroozan, R., Sadun, A., Karanjia, R.,
Biochemical and Biophysical Research Communications, 234, 511–515. Jurkute, N., Blouin, L., Taiel, M., Sahel, J. A., Hussain, R., … Pina, A.
https://doi.org/10.1006/bbrc.1997.6660 (2022). Natural history of patients with Leber hereditary optic
Wolf, D. P., Mitalipov, N., & Mitalipov, S. (2015). Mitochondrial replacement neuropathy—Results from the REALITY study. Eye (Basingstoke),
therapy in reproductive medicine. Trends in Molecular Medicine, 21, 36(4), 818–826. https://doi.org/10.1038/s41433-021-01535-9
68–76. https://doi.org/10.1016/j.molmed.2014.12.001 Zacksenhaus, E., Shrestha, M., Liu, J. C., Vorobieva, I., Chung, P. E. D.,
Wu, M., Gu, J., Guo, R., Huang, Y., & Yang, M. (2016). Structure of Ju, Y. J., Nir, U., & Jiang, Z. (2017). Mitochondrial OXPHOS induced
mammalian respiratory supercomplex I1III2IV1. Cell, 167, by RB1 deficiency in breast cancer: Implications for anabolic
1598–1609. https://doi.org/10.1016/j.cell.2016.11.012 metabolism, stemness, and metastasis. Trends in Cancer, 3,
Xiaohang, Y., & Trumpower, B. L. (1986). Purification of a three‐subunit 768–779. https://doi.org/10.1016/j.trecan.2017.09.002
ubiquinol‐cytochrome c oxidoreductase complex from Paracoccus Zhao, R. Z., Jiang, S., Zhang, L., & Yu, Z. B. (2019). Mitochondrial electron
denitrificans. Journal of Biological Chemistry, 261(26), 12282–12289. transport chain, ROS generation and uncoupling (review).
https://doi.org/10.1016/S0021-9258(18)67236-9 International Journal of Molecular Medicine, 44(1), 3–15. https://doi.
Yadav, N., & Chandra, D. (2013). Mitochondrial DNA mutations and breast org/10.3892/ijmm.2019.4188
tumorigenesis. Biochimica et Biophysica Acta—Reviews on Cancer, Zhao, Y. B., Yang, H. Y., Zhang, X. W., & Chen, G. Y. (2005). Mutation in D‐
1836(2), 336–344. https://doi.org/10.1016/j.bbcan.2013.10.002 loop region of mitochondrial DNA in gastric cancer and its
Yang, J., Zhu, Y., Chen, L., Zhang, H., Tong, Y., Huang, D., Zhang, Z., significance. World Journal of Gastroenterology, 11, 3304–3306.
Chen, S., Han, X., & Ma, X. (2009). Novel A14841G mutation is https://doi.org/10.3748/wjg.v11.i21.3304
associated with high penetrance of LHON/C4171A family. Zhou, S., Kachhap, S., Sun, W., Wu, G., Chuang, A., Poeta, L., Grumbine, L.,
Biochemical and Biophysical Research Communications, 386, Mithani, S. K., Chatterjee, A., Koch, W., Westra, W. H., Maitra, A.,
693–696. https://doi.org/10.1016/j.bbrc.2009.06.102 Glazer, C., Carducci, M., Sidransky, D., McFate, T., Verma, A., &
Yankovskaya, V., Horsefield, R., Törnroth, S., Luna‐Chavez, C., Miyoshi, H., Califano, J. A. (2007). Frequency and phenotypic implications of
Léger, C., Byrne, B., Cecchini, G., & Iwata, S. (2003). Architecture of mitochondrial DNA mutations in human squamous cell cancers of
succinate dehydrogenase and reactive oxygen species generation. the head and neck. Proceedings of the National Academy of Sciences of
Science, 299, 700–704. https://doi.org/10.1126/science.1079605 the United States of America, 104(18), 7540–7545. https://doi.org/
Yao, Y., Nishimura, M., Murayama, K., Kuranobu, N., Tojo, S., Beppu, M., 10.1073/pnas.0610818104
Ishige, T., Itoga, S., Tsuchida, S., Mori, M., Takayanagi, M., Zhou, X., Wei, Q., Yang, L., Tong, Y., Zhao, F., Lu, C., Qian, Y., Sun, Y.,
Yokoyama, M., Yamagata, K., Kishita, Y., Okazaki, Y., Nomura, F., Lu, F., Qu, J., & Guan, M. X. (2006). Leber's hereditary optic
Matsushita, K., & Tanaka, T. (2019). A simple method for sequencing neuropathy is associated with the mitochondrial ND4 G11696A
the whole human mitochondrial genome directly from samples and mutation in five Chinese families. Biochemical and Biophysical
its application to genetic testing. Scientific Reports, 9, 17411. https:// Research Communications, 340(1), 69–75. https://doi.org/10.1016/
doi.org/10.1038/s41598-019-53449-y j.bbrc.2005.11.150
Yiş, U., Ezgü, F. S., Karakaya, P., Polat, I., Arslan, N., Çankaya, T., Zhu, J., Vinothkumar, K. R., & Hirst, J. (2016). Structure of mammalian
Bozkaya, Ö. G., & Kurul, S. H. (2015). A novel mutation in the respiratory complex I. Nature, 536, 354–358. https://doi.org/10.
mitochondrial DNA cytochrome b gene (MTCYB) in a patient with 1038/nature19095
prader willi syndrome. Journal of Child Neurology, 30, 378–381.
https://doi.org/10.1177/0883073814530499
Yoon, K. L., Modica‐Napolitano, J. S., Ernst, S. G., & Aprille, J. R. (1991).
Denaturing gradient gel method for mapping single base changes in
How to cite this article: Vikramdeo, K. S., Sudan, S. K., Singh,
human mitochondrial DNA. Analytical Biochemistry, 196, 427–432.
https://doi.org/10.1016/0003-2697(91)90489-G A. P., Singh, S., & Dasgupta, S. (2022). Mitochondrial
Yu, M. (2011). Generation, function and diagnostic value of mitochondrial respiratory complexes: Significance in human mitochondrial
DNA copy number alterations in human cancers. Life Sciences, disorders and cancers. Journal of Cellular Physiology, 237,
89(3–4), 65–71. https://doi.org/10.1016/j.lfs.2011.05.010
4049–4078. https://doi.org/10.1002/jcp.30869
Yuan, R. T., Sun, Y., Bu, L. X., & Jia, M. Y. (2015). Gene mutations in the
D‐loop region of mitochondrial DNA in oral squamous cell

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10974652, 2022, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jcp.30869 by Conricyt Fondo Institucional Del Conacyt, Wiley Online Library on [06/01/2023].

Mitochondrial respiratory complexes: Significance in human

Kunwar Somesh Vikramdeo1,2 | Sarabjeet Kour Sudan1,2 | Ajay P. Singh1,2,3 |

1 | INTRODUCTION (OXPHOS) system involves the generation of NADH and FADH2

J Cell Physiol. 2022;237:4049–4078. wileyonlinelibrary.com/journal/jcp © 2022 Wiley Periodicals LLC. | 4049

F I G U R E 2 The mtDNA homoplasmy and

2 | R C M A C H I N E R Y AN D T H E OX P H O S translocation and UbQ binding are thought to perform by mtDNA‐

Gene Mutation Disease References

c.111G>C Progressive neurodegeneration

NDUFA2 c.208G>A LS Hoefs et al. (2008)

NDUFA8 325G>A LS Bugiani et al. (2004)

NDUFA9 c.962G>C LS van den Bosch et al. (2012)

NDUFA10 c.1A>G + c.425A>G LS Haack et al. (2012)

c.296G>A Muscular hypotonia

NDUFA12 c.178C>T LS Ostergaard et al. (2011)

NDUFA13 c.107T>C LS González‐Quintana

NDUFB9 c.191T>C Muscular hypotonia Haack et al. (2012)

NDUFS1 c.212T>A + c.384T>A Muscular hypotonia Bugiani et al. (2004);

c.721C>T Unspecified encephalomyopathy

c.1669C>T + c.1783A>G Leukodystrophy

c.1699C>T + c.631‐ Leukoencephalopathy

c.1783A>G Progressive cavitating Leukoencephalopathy

c.1912INS.A + c.2084A>G Leukodystrophy

c.2083T>C + c.2084A>G Leukodystrophy

NDUFS2 c.58C>A Encephalomyopathy Bugiani et al. (2004);

c.671C>T Severe neonatal hypotonia, dysmorphic

c.683G>A Hypertrophic cardiomyopathy and

Gene Mutation Disease References

c.875T>C + c.866 + 4A>G LS‐like

NDUFS3 c.434C>T + c.595C>T LS Bénit et al. (2004)

c.668C>T Unspecified encephalomyopathy

NDUFS4 c.9‐1G>A9 LS‐like Budde et al. (2003);

c.355G>C + c.462delA LS‐like

c.466–470Ins.AAGTC Unspecified encephalomyopathy

NDUFS6 c.186 + 2T>A Lethal infantile mitochondrial disease Kirby, McFarland,

c.344G>A Neonatal lactic academia

c.352C>T Muscular hypotonia

NDUFS7 c.17‐1167C>G LS Triepels et al. (1999)

NDUFS8 c.52C>T Encephalomyopathy Procaccio and

c.460G>A (+c.826G>A) Leukoencephalopathy

NDUFV1 c.175C>T + 1268C>T Progressive unspecified encephalomyopathy Calvo et al. (2010)

c.611A>G + c.616T>G LS‐like/LS

c.632C>T Hypotonia and lactic acidosis

c.770G >A + 632T>C Leukoencephalopathy

Gene Mutation Disease References

c.1129G>A Lethal infantile mitochondrial disease

NDUFV2 c.86C>T Encephalomyopathy Laugel et al. (2007;

SDHA c.64‐2A>G Leigh syndrome Alston et al. (2012);

c.G117G/del Mitochondrial encephalopathy

SDHB c.143A>T Leukodystrophy Alston et al. (2012)

3796A>G Adult‐onset dystonia

MT‐ND2 4681T>C LS Brown et al. (1995);

MT‐ND3 10158T>C LS McFarland et al. (2004);

MT‐ND4L 10663T>C LHON Abu‐Amero

MT‐ND4 11232T>C Chronic progressive external ophthalmoplegia Deschauer et al. (2003);

Gene Mutation Disease References

11994C>T Low sperm motility

MT‐ND5 12706T>G LS Engvall et al. (2021);

13063G > A Leigh