title: VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.
abstract: Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget's disease, or a combination of these. The disease mechanism is unknown. We developed a Drosophila model of VCP mutation-dependent degeneration. The phenotype is reminiscent of PINK1 and parkin mutants, including a pronounced mitochondrial defect. Indeed, VCP interacts genetically with the PINK1/parkin pathway in vivo. Paradoxically, VCP complements PINK1 deficiency but not parkin deficiency. The basis of this paradox is resolved by mechanistic studies in vitro showing that VCP recruitment to damaged mitochondria requires Parkin-mediated ubiquitination of mitochondrial targets. VCP recruitment coincides temporally with mitochondrial fission, and VCP is required for proteasome-dependent degradation of Mitofusins in vitro and in vivo. Further, VCP and its adaptor Npl4/Ufd1 are required for clearance of damaged mitochondria via the PINK1/Parkin pathway, and this is impaired by pathogenic mutations in VCP.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38120, USA.
authors.forename: Nam Chul
authors.initials: NC
authors.lastname: Kim
authors.forename: Emilie
authors.initials: E
authors.lastname: Tresse
authors.forename: Regina-Maria
authors.initials: RM
authors.lastname: Kolaitis
authors.forename: Amandine
authors.initials: A
authors.lastname: Molliex
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Thomas
authors.forename: Nael H
authors.initials: NH
authors.lastname: Alami
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Aashish
authors.initials: A
authors.lastname: Joshi
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Smith
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Ritson
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Winborn
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moore
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.forename: Leo
authors.initials: L
authors.lastname: Pallanck
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D061209:Proton Ionophores / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D000074405:Valosin Containing Protein; D000099202:PTEN-Induced Putative Kinase
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D020558:GTP Phosphohydrolases; D050884:HSP72 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D008164:Luminescent Proteins; D033681:Mitochondrial Membrane Transport Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011506:Proteins; D061209:Proton Ionophores; D034741:RNA, Small Interfering; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000074405:Valosin Containing Protein; C557617:GAL4 protein, Drosophila; C514112:NPLOC4 protein, human; C491497:UFD1 protein, human; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C540051:EDTP protein, Drosophila; C000614178:VCP protein, human; C470017:Mfn1 protein, human; C487430:park protein, Drosophila; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde