A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine-expanded protein
A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine-expanded protein
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DOI：
10.1016/j.mito.2010.09.001
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发表时间：
2011-01-01
期刊：
影响因子：
4.4
通讯作者：
Yanagi, Shigeru
中科院分区：
文献类型：
--
作者：
Sugiura, Ayumu;Yonashiro, Ryo;Yanagi, Shigeru
ataxin-3 （polyQ）中聚谷氨酰胺束的扩张导致Machado-Joseph病，这是一种以泛素阳性聚集形成为特征的晚发性神经退行性疾病。几条线索的证据表明，polyQ也在线粒体中积累并导致线粒体！功能障碍。为了揭示泛素-蛋白酶体途径对线粒体质量控制的机制，我们研究了位于线粒体外膜的一种新型线粒体泛素连接酶MITOL是否参与线粒体致病性ataxin-3的降解。在本研究中，我们使用n端截断的致病性ataxin-3与71-谷氨酰胺重复序列（Delta NAT-3Q71），发现MITOL通过泛素-蛋白酶体途径促进Delta NAT-3Q71的降解，并减弱Delta NAT-3Q71的线粒体积累。相反，MITOL敲低诱导不溶性清洁剂的Delta nat3q71积聚，形成大聚集体，导致细胞色素c释放和随后的细胞死亡。因此，MITOL对多q毒性具有保护作用，因此可能是治疗多q疾病的潜在靶点。我们的研究结果表明，线粒体外膜通过mitol介导的泛素-蛋白酶体途径存在蛋白质质量控制机制。(C) 2010 Elsevier B.V.和线粒体研究学会。版权所有。
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. (C) 2010 Elsevier B.V. and Mitochorndria Research Society. All rights reserved.