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

作者：Sugiura Ayumu; Yonashiro Ryo; Fukuda Toshifumi; Matsushita Nobuko; Nagashima Shun; Inatome Ryoko; Yanagi Shigeru^*

来源：Mitochondrion, 2011, 11(1): 139-146.

DOI：10.1016/j.mito.2010.09.001

• MITOL
• Mitochondrial ubiquitin ligase
• PolyQ
• Mitochondrial quality-control
• ERAD
• Apoptosis

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 mitochondria! 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 (Delta NAT-3Q71) and found that MITOL promoted Delta NAT-3Q71 degradation via the ubiquitin-proteasome pathway and attenuated mitochondrial accumulation of Delta NAT-3Q71. Conversely, MITOL knockdown induced an accumulation of detergent-insoluble Delta NAT-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.

• 出版日期2011-1