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FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors
FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors
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Length:
20 minutes
Released:
Oct 12, 2022
Format:
Podcast episode
Description
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.10.12.511867v1?rss=1
Authors: Pagan, J., Nguyen-Dien, G., Kozul, K., Cui, Y., Townsend, B., Ooi, S. S., Pagano, M., Lazarou, M., Taylor, R., Collins, B. M., Parton, R. G., Kulkarni, P., Carrodus, N., Zuryn, S., Millard, S., Marzio, A., Jones, M.
Abstract:
Cells selectively remove damaged or excessive mitochondria through mitophagy, a specialized form of autophagy, to maintain mitochondrial quality and quantity. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation, and mitochondrial damage. However, the mechanisms by which cells remove specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box protein ubiquitin ligase complex, localizes to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that, unlike wild-type FBXL4, pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13), do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism that actively suppresses mitophagy via preventing NIX and BNIP3 accumulation and propose that excessive basal mitophagy in the FBXL4-associated mtDNA depletion syndrome is caused by dysregulation of NIX and BNIP3 turnover.
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http://biorxiv.org/cgi/content/short/2022.10.12.511867v1?rss=1
Authors: Pagan, J., Nguyen-Dien, G., Kozul, K., Cui, Y., Townsend, B., Ooi, S. S., Pagano, M., Lazarou, M., Taylor, R., Collins, B. M., Parton, R. G., Kulkarni, P., Carrodus, N., Zuryn, S., Millard, S., Marzio, A., Jones, M.
Abstract:
Cells selectively remove damaged or excessive mitochondria through mitophagy, a specialized form of autophagy, to maintain mitochondrial quality and quantity. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation, and mitochondrial damage. However, the mechanisms by which cells remove specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box protein ubiquitin ligase complex, localizes to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that, unlike wild-type FBXL4, pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13), do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism that actively suppresses mitophagy via preventing NIX and BNIP3 accumulation and propose that excessive basal mitophagy in the FBXL4-associated mtDNA depletion syndrome is caused by dysregulation of NIX and BNIP3 turnover.
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/511867v1_ufig1.gif" ALT="Figure 1" greater than
View larger version (60K):
[email protected]@1d39846org.highwire.dtl.DTLVardef@b23b60org.highwire.dtl.DTLVardef@1582329_HPS_FORMAT_FIGEXP M_FIG C_FIG
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Oct 12, 2022
Format:
Podcast episode
Titles in the series (100)
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