A LON-ClpP Proteolytic Axis Degrades Complex I to Extinguish ROS Production in Depolarized Mitochondria.
A LON-ClpP Proteolytic Axis Degrades Complex I to Extinguish ROS Production in Depolarized Mitochondria.
复制标题
DOI：
10.1016/j.celrep.2016.11.027
复制
发表时间：
2016-12-06
期刊：
影响因子：
8.8
通讯作者：
Schapira AH
中科院分区：
文献类型：
--
作者：
Pryde KR;Taanman JW;Schapira AH
线粒体功能障碍涉及许多神经退行性疾病，特别是帕金森病（PD）。PINK 1和Parkin基因突变是常染色体隐性遗传PD的原因，并且这些各自的蛋白质协同作用以降解去极化的线粒体（线粒体自噬）。人们普遍认为，受损的线粒体自噬导致PD，因为产生毒性活性氧（ROS）的线粒体积累并逐渐驱动神经退行性变。相反，我们报告说，LON-ClpP蛋白水解质量控制轴通过降解复合物I ROS生成结构域来消除去极化线粒体中的ROS。在PD脑中也发现了复合物I缺乏症，我们的研究提供了一个令人信服的非遗传机制理论来解释这一观察结果：如果线粒体生物能量能力强烈减弱，则完整的复合物I耗尽。复合物I选择性地易受去极化线粒体中的蛋白水解的影响，如果线粒体自噬失败，复合物I降解会导致高ROS，在线粒体应激诱导后，LON和ClpP结合并降解复合物I。复合物I丰度与线粒体稳态偶联。Pryde等人相反，显示了这些细胞器中蛋白水解质量控制增强物通过降解复合物I的ROS产生结构域来限制和减少ROS。
Mitochondrial dysfunction is implicated in numerous neurodegenerative disorders and in Parkinson’s disease (PD) in particular. PINK1 and Parkin gene mutations are causes of autosomal recessive PD, and these respective proteins function cooperatively to degrade depolarized mitochondria (mitophagy). It is widely assumed that impaired mitophagy causes PD, as toxic reactive oxygen species (ROS)-producing mitochondria accumulate and progressively drive neurodegeneration. Instead, we report that a LON-ClpP proteolytic quality control axis extinguishes ROS in depolarized mitochondria by degrading the complex I ROS-generating domain. Complex I deficiency has also been identified in PD brain, and our study provides a compelling non-genetic mechanistic rationale to explain this observation: intact complex I depletes if mitochondrial bioenergetic capacity is robustly attenuated. Complex I is selectively vulnerable to proteolysis in depolarized mitochondria Complex I degradation extinguishes high ROS if mitophagy fails LON and ClpP bind and degrade complex I after mitochondrial stress induction Complex I abundance is coupled to mitochondrial homeostasis Damaged mitochondria are thought to accumulate if mitophagy is impaired and to cause Parkinson’s disease by continuously generating high levels of toxic reactive oxygen species (ROS). Pryde et al. show instead that proteolytic quality control ensues in these organelles to confine and diminish ROS by degrading the ROS-producing domain of complex I.
登录
查看更多内容
线粒体中复合物I的基质臂的低丰度预测小鼠的寿命。
影响因子：
16.6
作者：
Miwa, Satomi;Jow, Howsun;Baty, Karen;Johnson, Amy;Czapiewski, Rafal;Saretzki, Gabriele;Treumann, Achim;von Zglinicki, Thomas
通讯作者：
von Zglinicki, Thomas
影响因子：
6.6
作者：
Gorenkova, Natalia;Robinson, Emma;Galkin, Alexander
通讯作者：
Galkin, Alexander
DOI：
10.1083/jcb.201402104
发表时间：
2014-04-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kane LA;Lazarou M;Fogel AI;Li Y;Yamano K;Sarraf SA;Banerjee S;Youle RJ
通讯作者：
Youle RJ
影响因子：
7.8
作者：
Lambert, Adrian J.;Buckingham, Julie A.;Brand, Martin D.
通讯作者：
Brand, Martin D.
影响因子：
6.6
作者：
Koopman, Werner J H;Nijtmans, Leo G J;Willems, Peter H G M
通讯作者：
Willems, Peter H G M