RRC ID 68916
Author McLelland GL, Soubannier V, Chen CX, McBride HM, Fon EA.
Title Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control.
Journal EMBO J
Abstract Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD.
Volume 33(4)
Pages 282-95
Published 2014-2-18
DOI 10.1002/embj.201385902
PII embj.201385902
PMID 24446486
PMC PMC3989637
MeSH Antimycin A / pharmacology Autophagy / physiology* Biological Transport Dynamins GTP Phosphohydrolases / antagonists & inhibitors GTP Phosphohydrolases / genetics Genes, Reporter HeLa Cells Humans Lysosomes / physiology Microtubule-Associated Proteins / antagonists & inhibitors Microtubule-Associated Proteins / genetics Mitochondria / physiology* Mitochondrial Proteins / antagonists & inhibitors Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism* Models, Biological Oxidation-Reduction Oxidative Stress Parkinson Disease / genetics Parkinson Disease / metabolism* Protein Kinases / physiology* Proteolysis RNA Interference RNA, Small Interfering / pharmacology Recombinant Fusion Proteins / metabolism Transport Vesicles / metabolism* Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / physiology*
IF 9.889
Human and Animal Cells Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711)