VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.
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.
Pubmed ID: 23498974 RIS Download
Adenosine Triphosphatases | Animals | Animals, Genetically Modified | Carbonyl Cyanide m-Chlorophenyl Hydrazone | Cell Cycle Proteins | Cells, Cultured | Drosophila | Drosophila Proteins | Embryo, Mammalian | Enzyme Inhibitors | GTP Phosphohydrolases | Ganglia, Spinal | Gene Expression Regulation | HSP72 Heat-Shock Proteins | Humans | Immunoprecipitation | In Vitro Techniques | Leupeptins | Luminescent Proteins | Microscopy, Electron, Transmission | Mitochondria | Mitochondrial Membrane Transport Proteins | Mutation | Neuromuscular Junction | Neurons | Nuclear Proteins | Protein Tyrosine Phosphatases | Protein-Serine-Threonine Kinases | Proteins | Proton Ionophores | RNA, Small Interfering | Time Factors | Transcription Factors | Transfection | Ubiquitin-Protein Ligases | Ubiquitination