მიტოქონდრიის ფუნქცია და კიბო
მიტოქონდრიის ფუნქცია და კიბო
მიტოქონდრიის ფუნქცია და კიბო
Douglas C. Wallace
In addition to compartmentalizing the metabolic pathways and physiological states of the cell, mitochondria generate much of the cellular energy, regulate the cellular oxidationreduction (redox) state, produce most of the cellular reactive oxygen species (ROS), buffer cellular Ca2+ and initiate cellular apoptosis. Mitochondria were first proposed to be relevant to cancer by Otto Warburg who reported that cancer cells exhibited aerobic glycolysis. Although this was originally interpreted as indicating that the function of the mitochondria was defective, we now understand that cancer cells are in an altered metabolic state with increased
HIF1
CANCER
Supplement to Nature Publishing Group
glycolytic metabolism and the continued use of oxygen. Mutations that occur in nuclear-DNA-encoded mitochondrial proteins and mitochondrial-DNA-encoded proteins can re-orient cellular metabolism towards glycolysis, glutaminolysis, intense macromolecular biogenesis and the oxidoreduction of NADP+ to NADPH. Both somatic and germline mitochondrial DNA mutations have been associated with many types of cancers, and recent data indicate that cancer cells may tolerate mitochondrial DNA mutations for two purposes: they alter cancer cell metabolism and/or proliferation and they enable adaption to a changing environment.
Altered energetics
HIF1
Fumarate PHD Succinate Pi ROS H+ I NADH H2O2 CoQ e NAD+ NADP+ NNT H+ NADPH GSSG H 2O
Acetyl-CoA
Redox regulation
ADP ATP VDAC F0 V ANT ADP ATP
Activation of the PI3KAKT pathway increases glucose uptake and metabolism. AKT phosphorylates and inactivates FOXO, downregulating PGC1 and reducing mitochondrial biogenesis. Activation of MYC induces glutaminolysis, in which glutamine is converted to -ketoglutarate (KG). Reductive carboxylation of KG to isocitrate can be facilitated by NADPH-linked IDH2, resulting in increased citrate synthesis. Mitochondrial citrate can be exported into the cytosol, where isocitrate can be converted to KG by NADP+-linked IDH1. Mutant IDH1 or IDH2 oxidize NADPH back to NADP+ and reduce KG to R()-2-hydroxyglutarate ((R)-2HG), an oncometabolite that affects DNA and histone methylation and HIF1 activity. SDH mutations disrupt the TCA cycle causing the accumulation of succinate and perhaps also increased ROS production. FH mutation causes the accumulation of succinate and fumarate, both of which can inhibit prolyl hydroxylases (PHDs) and stabilize HIF1. In addition, fumarate can succinylate and inactivate KEAP1, resulting in the activation of NRF2. This induces stress-response genes including HMOX1, which degrades haem to bilirubin. This removes excess succinyl-CoA by condensation with glycine to generate -aminolevulinic acid (ALA), the commitment step of NAD+ Fatty acid haem biosynthesis. Mutated enzymes are shown in orange. synthesis
Citrate
CuZnSOD II
H IV
O2 (GSH)2
O2
Citrate Isocitrate
Oxaloacetate
Mitochondrial DNA is essential for cancer cells and copy number alterations and inherited and somatic mutations can modify mitochondrial function
Nicotinamide nucleotide transhydrogenase (NNT) uses the energy of the mitochondrial membrane potential to transfer reducing equivalents from NADP+ to NADPH. The increased reducing potential of NADPH is then used to reduce oxidized glutathione for the reduction of H2O2 to H2O, change the thiol-disulfide balance of amino acids in proteins to regulate transcription factors and enzymes, and to drive macromolecular synthesis. Cytosolic NADPH can be generated by the BCL-2 pentose phosphate shunt, by the conversion of malate to pyruvate and by the action of IDH1. Alteration of these Cyt c pathways can increase ROS levels and alter cellular metabolism and growth. SMAC
BAX BAX Cell death
Isocitrate FOSJUN (SH)2 FOSJUN (SO)2 Nucleus APEOx APERed TRX1 (SH)2 TRX1 (SS) NADP+ NADPH IDH1
NADP+ NADPH
ATP-citrate lyase Malate FH Fumarate PDH SDH IV PKC Cyt c Retinol p66SHC Pyruvate LDHA NRF2 KEAP1 PKM2 PKM2 PKM2 PKM2 PKM2 PKM2 AKT P Phosphoenolpyruvate Lactate Acetyl-CoA V F0 NADP+ NADPH Citrate
Acetyl-CoA Oxaloacetate
Biogenesis
IDH2
-ketoglutarate NADPH Increased glycolysis Increased vascularization Induction of mitophagy Induction of COX4-2 Inhibition of COX4-1 Inhibition of PDH IDH1 NADP+ (R)-2HG Eects KG-dependent enzymes, DNA methylation, histone methylation and HIF1 Glycine
Malate
Succinyl-CoA
NADP+
HIF1 HIF1
MXI1
HIF1 HIF1
ALA
Protein synthesis
FOXO3A MYC Glutaminolysis, nucleotide synthesis, LDHA expression and bioenergetic pathways
AMPK
CREB
FOXO3A
LKB1 Macromolecular synthesis 3-phosphoglycerate Glycolysis NADPH NADP+ Glutamine transporter, such as SLC1A5 Glutamine Pentose phosphate pathway and nucleotide synthesis PTEN Glucose-6-phosphate TIGAR PI3K
Author address
Douglas C. Wallace, Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Disease and Director of the Center for Mitochondrial and Epigenomic Medicine (CMEM), Children's Hospital of Philadelphia. Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Colket Translational Research Building, Room 6060, 3501 Civic Center Boulevard, Philadelphia, PA 19104 E-mail: wallaced1@email.chop.edu DCW and the Children's Hospital of Philadelphia are not affiliated with Abcam.
ANT; adenine nucleotide transporter; CHCHD4, coiled-coilhelixcoiled-coil-helix domain-containing protein 4; CoQ, coenzyme Q; COX, cyctochrome c oxidase; CuZnSOD, copperzinc superoxide dismutase; Cyt c, cytochrome c; ETC, electron transport chain; FH, Fumarate hydratase; G6P, glucose 6-phosphate; GLUT1, glucose transporter 1; GSH, reduced glutathione; HIF1, hypoxia-inducible factor 1; HMOX1, haemoxygenase 1; IDH, isocitrate dehydrogenase; KEAP1; kelch-like ECH-associated protein 1; LDHA, lactate dehyrogenase A; LKB1, liver kinase B1; MnSOD, manganese superoxide dismutase; NNT, nicotinamide nucleotide
Abbreviations
transhydrogenase; NRF2, nuclear factor erythroid related factor 2; PDH, pyruvate dehydrogenase; PGC1, peroxisome proliferator-activated receptor- coactivator 1; ROS, reactive oxygen species; SCL1A5, solute carrier family 1 (neutral amino acid transporter) member 5; SDH, succinate dehydrogenase TIGAR, TP53-induced glycolysis and apoptosis regulator; TRX, thioredoxin; TSC1, hamartin; TSC2, tuberin; VDAC, voltage-dependent anion channel. Edited by Nicola McCarthy; copyedited by Darren Burgess; designed by Lara Crow. 2012 Nature Publishing Group. http://www.nature.com/reviews/poster/mitochondria