title: VCP cooperates with UBXD1 to degrade mitochondrial outer membrane protein MCL1 in model of Huntington's disease.
abstract: Proteasome-dependent turnover of mitochondrial outer membrane (OMM)-associated proteins is one of the mechanisms for maintaining proper mitochondrial quality and function. However, the underlying pathways and their implications in human disease are poorly understood. Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by expanded CAG repeats in the N terminal of the huntingtin gene (mutant Huntingtin, mtHtt). In this study, we show an extensive degradation of the OMM protein MCL1 (Myeloid cell leukemia sequence 1) in both HD mouse striatal cells and HD patient fibroblasts. The decrease in MCL1 level is associated with mitochondrial and cellular damage. Valosin-containing-protein (VCP) is an AAA-ATPase central to protein turnover via the ubiquitin proteasome system (UPS). We found that VCP translocates to mitochondria and promotes MCL1 degradation in HD cell cultures. Either down-regulation of VCP by RNA interference or inhibition of VCP by a dominant negative mutant abolishes MCL1 degradation in HD cell cultures. We further show that UBX-domain containing protein 1 (UBXD1), a known co-factor of VCP assisting in the recognition of substrates for protein degradation, selectively binds to MCL1 and interacts with VCP to mediate MCL1 extraction from the mitochondria. These results indicate that the OMM protein MCL1 is degraded by the VCP-UBXD1 complex and that the process is promoted by the presence of mtHtt. Therefore, our finding provides a new insight into the mechanism of mitochondrial dysfunction in HD.
authors.affiliation: Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Center for Mitochondrial Disease, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: xxq38@case.edu.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D059748:Proteolysis; D000074405:Valosin Containing Protein / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C533572:UBXN6 protein, human; C000629263:Ubxn6 protein, mouse; D033921:Vesicular Transport Proteins; D000074405:Valosin Containing Protein
keywords: Huntington's disease; Mitochondria; Protein degradation; Valosin-containing protein