A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine-expanded protein

• Published in: Mitochondrion 2011-01, Vol.11 (1), p.139-146
• Main Authors: Sugiura, Ayumu, Yonashiro, Ryo, Fukuda, Toshifumi, Matsushita, Nobuko, Nagashima, Shun, Inatome, Ryoko, Yanagi, Shigeru
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Chlorocebus aethiops; COS Cells - drug effects; Gene Expression Regulation; Humans; Intracellular Membranes - metabolism; Machado-Joseph Disease - metabolism; Machado-Joseph Disease - pathology; Membrane Proteins; Mitochondria - enzymology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - toxicity; Neurons - drug effects; Peptides - chemistry; Peptides - metabolism; Peptides - toxicity; Proteasome Endopeptidase Complex - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1567-7249; 1872-8278
• DOI: 10.1016/j.mito.2010.09.001

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.