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A Proteolytic Hub in Mitochondria Regulating Mitophagy and Cell Death

线粒体中调节线粒体自噬和细胞死亡的蛋白水解中心

基本信息

批准号：
274447724
负责人：
Professor Dr. Thomas Langer
金额：
--
依托单位：
Max-Planck-Institut für Biologie des Alterns
依托单位国家：
德国
项目类别：
Reinhart Koselleck Projects
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/274447724?language=en
关键词：
Proteolytic Hub Mitochondria Regulating Mitophagy

项目摘要

A dysfunction of mitochondria, essential cell organelles surrounded by two membranes, is associated with aging and causes various diseases including cardiomyopathies and prevalent neurodegenerative disorders. The integrity of mitochondria depends on evolutionarily conserved proteases that serve quality control functions and regulate the biogenesis and dynamic behavior of mitochondria. An increasing number of substrates are reported to undergo proteolytic processing In the inner membrane, often followed by their redistribution within mitochondria. These proteins have been shown to regulate mitochondrial membrane dynamics, mitophagy and cell death. We have identified a large proteolytic hub, termed the SPY complex, which is composed of the membrane scaffold SLP2 and the mitochondrial proteases PARL and YME1L. SPY complexes were found to be essential for mitophagy and apoptotic as well as necrotic cell death, suggesting that these processes are regulated within spatially defined membrane domains in mitochondria. We will combine studies in cells and mice with advanced proteomic approaches to characterize these proteolytic hubs, to unravel the function of proteolytic processing of key regulatory proteins, and reveal how SPY complexes coordinate the activity of its resident oteases to modulate cell survival-cell death decisions.

线粒体是被两层膜包裹的基本细胞器，线粒体的功能障碍与衰老有关，并导致包括心肌病和普遍存在的神经退行性疾病在内的各种疾病。线粒体的完整性依赖于进化上保守的蛋白水解酶，这些酶具有质量控制功能，并调节线粒体的生物发生和动态行为。据报道，越来越多的底物在内膜进行蛋白质分解处理，随后它们通常在线粒体内重新分布。这些蛋白质已被证明调节线粒体膜动力学、有丝分裂和细胞死亡。我们已经确定了一个大型的蛋白分解中心，称为SPY复合体，它由膜支架SLP2和线粒体蛋白PAR1和YME1L组成。SPY复合体被发现对有丝分裂、凋亡和坏死性细胞死亡是必不可少的，这表明这些过程是在线粒体空间定义的膜域内调节的。我们将结合细胞和小鼠的研究与先进的蛋白质组学方法来表征这些蛋白分解中心，揭示关键调控蛋白的蛋白分解处理的功能，并揭示SPY复合体如何协调其驻留的Otease的活性来调节细胞生存-细胞死亡决定。