A Conserved Metalloprotease Required for Mitochondrial Maintenance and Protection

线粒体维护和保护所需的保守金属蛋白酶

• 批准号: 9277480
• 负责人: Oleh Khalimonchuk
• 金额: $ 27.32万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277480
• 关键词: Age; Aging; Alpha Cell; Amino Acids; Amyotrophic Lateral Sclerosis; Animal Model; Ataxia; Biochemical; Biogenesis; C-terminal; Cardiovascular Diseases; Cell Aging; Cells; Cellular Stress; Cellular biology; Complex; Data; Defect; Degenerative Disorder; Detection; Development; Disease; Eukaryota; Foundations; Future; Genes; Genetic; Goals; Growth; Health; Healthcare Systems; Homeostasis; Human; Individual; Inner mitochondrial membrane; Late-Onset Disorder; Lead; Link; Maintenance; Mammalian Cell; Mediating; Membrane; Membrane Potentials; Metalloproteases; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Chaperones; Molecular Target; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Parkinsonian Disorders; Patients; Peptide Hydrolases; Peripheral Nervous System Diseases; Physiological; Population; Preventive; Protein Chemistry; Proteins; Quality Control; Research; Role; Saccharomyces cerevisiae; Sirolimus; Site; Social Welfare; Spastic Paraplegia; Stress; System; Therapeutic; Therapeutic Intervention; Thermogenesis; Yeasts; Zebrafish; age related; base; cancer type; combat; genetic analysis; human disease; innovation; loss of function mutation; misfolded protein; mouse model; nervous system disorder; novel; polypeptide; protein protein interaction; proteostasis; public health relevance; respiratory; response; reverse genetics; stem; stress management; tool; yeast genetics

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.

描述（由申请人提供）：由于线粒体蛋白质稳态、膜电位和动力学改变而引起的许多遗传和年龄相关疾病强调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，线粒体福利通过多种相互依赖的机制得以维持，其中包括线粒体内质量控制 (IMQC)。 IMQC 包含一组进化保守的蛋白酶，可消除受损或多余的蛋白质，并通过加工调节多肽来介导协调反应。对于 IMQC 模块如何感知损伤并保护线粒体福利的理解存在重大差距。这是一个重要且重要的问题，因为 IMQC 的缺陷会导致毁灭性的神经退行性疾病，包括痉挛性截瘫、共济失调、帕金森症和潜在的肌萎缩侧索硬化症 (ALS)。早期研究表明保守的蛋白酶 Oma1 是 IMQC 的关键成分。 Oma1 是一种独特的内膜结合金属蛋白酶，参与线粒体功能障碍的感知；然而，其机制尚不清楚。一些观察结果表明，Oma1 在正常条件下以潜伏状态存在，并在响应稳态损伤（例如膜电位变化、氧化应激和呼吸衰退）时被激活。这些发现对线粒体质量控制具有广泛的影响，并为确定应激触发的 Oma1 激活机制以及 IMQC 如何感知线粒体损伤并促进应激管理和生存提供了良好的基础。中心假设是 Oma1 通过寡聚复合物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，可以感知线粒体功能障碍，并通过与其他 QC 分子合作，整合到全细胞应激保护机制中。这项研究的总体目标是确定 Oma1 及其功能性相互作用组有助于应激或衰老细胞中损伤感知和维持线粒体健康的分子机制。使用酵母遗传学、细胞生物学和蛋白质化学等不同领域的分子工具和方法的独特组合，将追求三个具体目标：（1）定义应激触发的 Oma1 激活机制； (2) 研究Oma1功能相互作用组的分子基础； (3) 确定 Oma1 中 ALS 相关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、细胞应激和退行性疾病（如 ALS）中的功能的普遍理解；并为未来考虑将 Oma1 作为针对这些疾病的潜在治疗干预的分子靶标提供基础。