title: Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.
abstract: Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Narendra
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Der-Fen
authors.initials: DF
authors.lastname: Suen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D005347:Fibroblasts / Q000201:enzymology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D009474:Neurons / Q000201:enzymology; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D014475:Uncoupling Agents; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse