title: A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine-expanded protein.
abstract: Expansion of a polyglutamine tract in ataxin-3 (polyQ) causes Machado-Joseph disease, a late-onset neurodegenerative disorder characterized by ubiquitin-positive aggregate formation. Several lines of evidence demonstrate that polyQ also accumulates in mitochondria and causes mitochondrial dysfunction. To uncover the mechanism of mitochondrial quality-control via the ubiquitin-proteasome pathway, we investigated whether MITOL, a novel mitochondrial ubiquitin ligase localized in the mitochondrial outer membrane, is involved in the degradation of pathogenic ataxin-3 in mitochondria. In this study, we used N-terminal-truncated pathogenic ataxin-3 with a 71-glutamine repeat (ΔNAT-3Q71) and found that MITOL promoted ΔNAT-3Q71 degradation via the ubiquitin-proteasome pathway and attenuated mitochondrial accumulation of ΔNAT-3Q71. Conversely, MITOL knockdown induced an accumulation of detergent-insoluble ΔNAT-3Q71 with large aggregate formation, resulting in cytochrome c release and subsequent cell death. Thus, MITOL plays a protective role against polyQ toxicity, and thereby may be a potential target for therapy in polyQ diseases. Our findings indicate a protein quality-control mechanism at the mitochondrial outer membrane via a MITOL-mediated ubiquitin-proteasome pathway.
authors.affiliation: Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Sugiura
authors.forename: Ryo
authors.initials: R
authors.lastname: Yonashiro
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Nobuko
authors.initials: N
authors.lastname: Matsushita
authors.forename: Shun
authors.initials: S
authors.lastname: Nagashima
authors.forename: Ryoko
authors.initials: R
authors.lastname: Inatome
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yanagi
mesh_terms: D000818:Animals; D019556:COS Cells / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D017827:Machado-Joseph Disease / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D025801:Ubiquitin; C097188:polyglutamine; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex