Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control.
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.
McGill Parkinson Program Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital McGill University, Montreal, QC, Canada.
Gian-Luca
GL
McLelland
Vincent
V
Soubannier
Carol X
CX
Chen
Heidi M
HM
McBride
Edward A
EA
Fon
D000968:Antimycin A / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology*; D001692:Biological Transport; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000502:physiology*; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D000099202:PTEN-Induced Putative Kinase
D000968:Antimycin A; D034281:Dynamins; D020558:GTP Phosphohydrolases; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C110768:DNM1L protein, human