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PMID:24446486

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Citation

McLelland, GL, Soubannier, V, Chen, CX, McBride, HM and Fon, EA (2014) Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 33:282-95

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.

Links

PubMed PMC3989637 Online version:10.1002/embj.201385902

Keywords

Antimycin A/pharmacology; Autophagy/physiology; Biological Transport; 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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PRKN

colocalizes_with

GO:0099073: mitochondrion-derived vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRKN

involved_in

GO:0099074: mitochondrion to lysosome transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN

involved_in

GO:1900407: regulation of cellular response to oxidative stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PINK1

involved_in

GO:0099074: mitochondrion to lysosome transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN2

involved_in

GO:1900407: regulation of cellular response to oxidative stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN2

colocalizes_with

GO:0099073: mitochondrion-derived vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

exists_during:(GO:0099074)

Seeded From UniProt

complete

HUMAN:PRKN2

involved_in

GO:0099074: mitochondrion to lysosome transport

ECO:0000314: direct assay evidence used in manual assertion

P

part_of:(GO:1900407)

Seeded From UniProt

complete

HUMAN:PINK1

involved_in

GO:1900407: regulation of cellular response to oxidative stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PINK1

involved_in

GO:0099074: mitochondrion to lysosome transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

part_of:(GO:1900407)

Seeded From UniProt

complete

Notes

See also

References

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