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: 8818735
• 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/8818735
• 关键词: Age; Aging; Amino Acids; Amyotrophic Lateral Sclerosis; Animal Model; Ataxia; Binding; 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; Maps; 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; Process; 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; cell age; combat; genetic analysis; human disease; innovation; late disease onset; loss of function mutation; mouse model; nervous system disorder; novel; polypeptide; positional cloning; protein misfolding; protein protein interaction; public health relevance; respiratory; response; 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）：源于线粒体蛋白质稳态、膜电位和动力学改变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、应激和重塑期间，线粒体的福利通过几种相互依存的机制来维持，其中包括线粒体内质量控制（IMQC）。IMQC包含一组进化上保守的蛋白酶，其消除受损或多余的蛋白质并通过加工调节多肽介导协调反应。在理解IMQC模块如何感知损伤和保护线粒体福利方面存在重大差距。这是一个重要且重要的问题，因为IMQC的缺陷表现在破坏性的神经退行性疾病中，包括痉挛性截瘫、共济失调、帕金森综合征和潜在的肌萎缩性侧索硬化症（ALS）。早期的研究表明，保守的蛋白酶Oma 1是IMQC的关键成分。Oma 1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，Oma 1在正常条件下以潜伏状态存在，并响应于稳态损伤（如膜电位变化、氧化应激和呼吸下降）而被激活。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Oma 1激活的机制以及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。核心假设是Oma 1通过其寡聚复合物的重塑被线粒体应激条件激活。Oma 1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分子的合作，整合到泛细胞应激保护机制中。本研究的总体目标是确定Oma 1及其功能性相互作用体有助于在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。利用酵母遗传学，细胞生物学和蛋白质化学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Oma 1激活的机制;（2）研究Oma 1功能相互作用组的分子基础;（3）确定Oma 1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Oma 1在健康，细胞应激和退行性疾病（如ALS）中功能的一般理解;并为未来考虑Oma 1作为针对这些疾病的潜在治疗干预的分子靶点提供基础。