A Proteolytic Hub in Mitochondria Regulating Mitophagy and Cell Death

线粒体（被两层膜包围的重要细胞器）的功能障碍与衰老有关，并导致各种疾病，包括心肌病和普遍的神经退行性疾病。线粒体的完整性依赖于进化上保守的蛋白酶，这些蛋白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中进行蛋白质水解处理，通常随后在线粒体内重新分布。这些蛋白已被证明调节线粒体膜动力学、线粒体自噬和细胞死亡。我们已经确定了一个大的蛋白水解中心，称为SPY复合体，它由膜支架SLP2和线粒体蛋白酶PARL和YME1L组成。SPY复合物被发现对线粒体自噬、凋亡和坏死细胞死亡至关重要，这表明这些过程在线粒体的空间限定膜结构域内受到调节。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水解中心，揭示关键调节蛋白的蛋白水解加工功能，并揭示SPY复合物如何协调其驻留酶的活性来调节细胞生存-细胞死亡决定。

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.