A Conserved Metalloprotease Required for Mitochondrial Maintenance and Protection

描述(由申请人提供)：由于线粒体蛋白稳态、膜电位和动力学的改变而引起的许多遗传和年龄相关疾病突出了线粒体功能完整性的重要性。在生物发生、应激和重塑过程中，线粒体福利通过几种相互依赖的机制来维持，其中包括线粒体内质量控制(IMQC)。IMQC由一组进化保守的蛋白水解酶组成，这些酶可以清除受损或多余的蛋白质，并通过处理调节多肽来调节协调反应。在理解IMQC模块如何感知损伤和保护线粒体福利方面存在严重差距。这是一个重大而重要的问题，因为IMQC的缺陷在毁灭性的神经退行性疾病中表现出来，包括痉挛性截瘫、共济失调、帕金森综合症和潜在的肌萎缩侧索硬化症(ALS)。早期的研究表明，保守的蛋白酶Oma1是IMQC的关键成分。Oma1是一种独特的内膜型金属蛋白水解酶，参与线粒体功能障碍的检测，但其作用机制尚不清楚。一些观察表明，Oma1在正常条件下以潜伏状态存在，并在膜电位变化、氧化应激和呼吸减弱等动态平衡损害时被激活。这些发现对线粒体质量控制具有广泛的意义，并为确定应激触发Oma1激活的机制以及IMQC如何感知线粒体损伤和促进应激管理和生存提供了良好的基础。中心假说是Oma1通过其寡聚体复合体的重塑而被线粒体应激条件激活。Oma1被认为是一个关键的IMQC模块，它可以感知线粒体的故障，并通过与其他QC分子的合作，整合到泛细胞应激保护机制中。这项研究的总体目标是确定Oma1及其功能相互作用组在应激或衰老细胞中促进损伤感知和维持线粒体健康的分子机制。利用酵母遗传学、细胞生物学和蛋白质化学等不同领域的独特分子工具和方法，将追求三个具体目标：(1)确定应激触发Oma1激活的机制；(2)研究Oma1功能相互作用组的分子基础；(3)确定Oma1中与ALS相关的突变对线粒体功能的净影响。这项创新研究的结果预计将影响对Oma1在健康、细胞压力和退行性疾病(如ALS)中功能的普遍理解；并为未来考虑将Oma1作为潜在的治疗这些疾病的分子靶标提供基础。

DESCRIPTION (provided by applicant): Numerous genetic and age-related diseases stemming from alterations in mitochondrial protein homeostasis, membrane potential, and dynamics highlight the significance of mitochondrial functional integrity. During biogenesis, stress, and remodeling, mitochondrial welfare is preserved by several interdependent mechanisms, which include the intramitochondrial quality control (IMQC). The IMQC comprises a set of evolutionary conserved proteases that eliminate damaged or surplus proteins and mediate coordinated responses by processing regulatory polypeptides. There are critical gaps in the understanding of how IMQC modules sense damage and preserve mitochondrial welfare. This is a significant and important problem, as defects of IMQC manifest in devastating neurodegenerative diseases, including spastic paraplegias, ataxias, Parkinsonism, and potentially Amyotrophic Lateral Sclerosis (ALS). Earlier studies have implicated the conserved protease Oma1 as a critical IMQC component. Oma1 is a unique inner membrane-bound metalloprotease involved in sensing of mitochondrial malfunction; however, the mechanism is not yet known. Several observations indicate that Oma1 exists in a latent state under normal conditions and is activated in response to homeostatic insults such as changes in membrane potential, oxidative stress, and respiratory decline. These findings have broad implications for mitochondrial quality control and provide an excellent foundation for determining the mechanism of stress-triggered Oma1 activation and how IMQC senses mitochondrial damage and promotes stress management and survival. The central hypothesis is that Oma1 is activated by mitochondrial stress conditions through remodeling of its oligomeric complex. Oma1 is postulated to be a key IMQC module that senses mitochondrial malfunction and, via cooperation with other QC molecules, integrates into pan-cellular stress protective mechanisms. The overall goal of this study is to define the molecular mechanisms by which Oma1 and its functional interactome contribute to damage sensing and maintenance of mitochondrial health in stressed or aging cells. Using a unique blend of molecular tools and approaches from the diverse fields of yeast genetics, cell biology, and protein chemistry, three specific aims will be pursued: (1) Define the mechanism of stress-triggered Oma1 activation; (2) Investigate the molecular basis of Oma1 functional interactome; and (3) Determine the net effects of ALS-associated mutations in Oma1 on mitochondrial function. The results of this innovative research are expected to impact general understanding of Oma1 function in health, cellular stress and degenerative diseases, such as ALS; and provide ground for future consideration of Oma1 as a molecular target for potential therapeutic interventions against these diseases.