title: Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.
abstract: Damage to mitochondria can lead to the depolarization of the inner mitochondrial membrane, thereby sensitizing impaired mitochondria for selective elimination by autophagy. However, fusion of uncoupled mitochondria with polarized mitochondria can compensate for damage, reverse membrane depolarization, and obviate mitophagy. Parkin, an E3 ubiquitin ligase that is mutated in monogenic forms of Parkinson's disease, was recently found to induce selective autophagy of damaged mitochondria. Here we show that ubiquitination of mitofusins Mfn1 and Mfn2, large GTPases that mediate mitochondrial fusion, is induced by Parkin upon membrane depolarization and leads to their degradation in a proteasome- and p97-dependent manner. p97, a AAA+ ATPase, accumulates on mitochondria upon uncoupling of Parkin-expressing cells, and both p97 and proteasome activity are required for Parkin-mediated mitophagy. After mitochondrial fission upon depolarization, Parkin prevents or delays refusion of mitochondria, likely by the elimination of mitofusins. Inhibition of Drp1-mediated mitochondrial fission, the proteasome, or p97 prevents Parkin-induced mitophagy.
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Megan M
authors.initials: MM
authors.lastname: Cleland
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.forename: Derek P
authors.initials: DP
authors.lastname: Narendra
authors.forename: Der-Fen
authors.initials: DF
authors.lastname: Suen
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D045744:Cell Line, Tumor; D034281:Dynamins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000251:Adenosine Triphosphatases; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D034281:Dynamins; D020558:GTP Phosphohydrolases; D007976:Leupeptins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011494:Protein Kinases; D034741:RNA, Small Interfering; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C079437:UBE2L3 protein, human; C515578:MARCHF5 protein, human; C111567:parkin protein; C470018:MFN2 protein, human; C415198:OPA1 protein, human; C404942:p97 ATPase; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde