Homeostatic Mechanisms Regulating Mitochondrial Health

调节线粒体健康的稳态机制

• 批准号: 10426098
• 负责人: David C Chan
• 金额: $ 65.6万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426098
• 关键词: Area; Astrocytes; Calcium; Cell physiology; Cells; Cellular biology; Complex; Defect; Development; Disease; Genes; Genetic Screening; Genome; Goals; Health; Human; Immunity; Iron; Knowledge; Lead; Longevity; Maintenance; Mediating; Membrane; Membrane Fusion; Metabolic Pathway; Mitochondria; Molecular; Morphology; Mus; Mutation; Nervous system structure; Nuclear; OPA1 gene; Organelles; Oxidative Phosphorylation; Pathway interactions; Physiological; Play; Population; Process; Protein Subunits; Proteins; Quality Control; Regulation; Research; Respiratory Chain; Role; Signal Transduction; Spermatocytes; Structure; Sulfur; biological systems; human disease; improved; innovation; interest; mitochondrial dysfunction; mitochondrial genome; programs; protein complex; public health relevance; stoichiometry

Project Summary/Abstract Mitochondria are essential organelles that are most well-known for being cellular "powerhouses," due to their role in oxidative phosphorylation (OXPHOS) and other metabolic pathways. In addition, they have diverse roles in other areas of cell biology, including calcium handling, immunity, cell signaling, and formation of iron-sulfur clusters. Healthy mitochondria are therefore critical for human health, and many common diseases are associated with mitochondrial dysfunction. The broad goal of this application is to understand the mechanisms that control mitochondrial health. There are three mechanisms of particular interest. First, mitochondrial function depends on continual cycles of fusion and fission. These dynamic processes serve to homogenize the mitochondrial population within a cell and are critical for maintenance of the mitochondrial genome, morphology, and respiratory chain activity. Second, mitophagy is a major mechanism to recognize and remove dysfunctional mitochondria. Third, protein surveillance mechanisms exist to maintain the quality of the OXPHOS protein complexes that generate cellular energy. The OXPHOS complexes are composed of protein subunits encoded by two genomes--the nuclear genome and the mitochondrial genome--and therefore have unique challenges in achieving proper subunit stoichiometry and assembly. This research program targets gaps in knowledge in each of these three homeostatic mechanisms. For mitochondrial dynamics, this research program investigates the molecular mechanisms and physiological functions of fusion and fission. To understand molecular mechanism, structural studies are used to obtain atomic structures of the key molecules mediating these processes. An example is Opa1, the molecule that mediates inner membrane fusion. Little is known about how this molecule is able to bring two inner membranes together and mediate membrane merger. To understand physiological function, mouse studies will be used to determine the role of mitochondrial fusion and fission. The application highlights two biological systems--the astrocytes of the nervous system and the male germ cell--in which mitochondrial fission and/or mitophagy play a prominent role. In the case of male germ cell development, mutations in mitochondrial dynamics genes lead to distinct stage-specific defects, providing a biological system in which multiple pathways requiring mitochondrial dynamics can be deciphered. To understand how the quality of the OXPHOS complexes are maintained, innovative genetic screens in human cells will be used to identify pathways that sense and degrade excessive subunits. Such quality control mechanisms have been implicated in lifespan regulation. Taken together, these approaches will provide a deep understanding of homeostatic mechanisms that maintain mitochondrial health.

项目概要/摘要 线粒体是重要的细胞器，因其作为细胞“发电站”而闻名，这是由于 它们在氧化磷酸化 (OXPHOS) 和其他代谢途径中的作用。此外，他们还有 在细胞生物学其他领域的多种作用，包括钙处理、免疫、细胞信号传导和 铁硫簇的形成。因此，健康的线粒体对人类健康至关重要，许多 常见疾病与线粒体功能障碍有关。该应用程序的总体目标是 了解控制线粒体健康的机制。具体机制有以下三种 兴趣。首先，线粒体功能取决于融合和裂变的持续循环。这些动态 该过程用于使细胞内的线粒体群体均质化，对于维持线粒体功能至关重要 线粒体基因组、形态和呼吸链活性。其次，线粒体自噬是一个重要的 识别和消除功能失调的线粒体的机制。三、蛋白质监测机制 其存在是为了维持产生细胞能量的 OXPHOS 蛋白复合物的质量。氧化磷 复合物由两个基因组（核基因组和核基因组）编码的蛋白质亚基组成。 线粒体基因组——因此在实现适当的亚基化学计量和 集会。该研究计划针对这三种稳态的知识差距 机制。对于线粒体动力学，该研究计划调查分子机制 以及融合和裂变的生理功能。了解分子机制、结构研究 用于获得介导这些过程的关键分子的原子结构。一个例子是 Opa1， 介导内膜融合的分子。人们对这种分子如何能够带来影响知之甚少 两个内膜结合在一起并介导膜合并。为了了解生理功能， 小鼠研究将用于确定线粒体融合和裂变的作用。应用 强调了两个生物系统——神经系统的星形胶质细胞和雄性生殖细胞——其中 线粒体裂变和/或线粒体自噬发挥着重要作用。就男性生殖细胞发育而言， 线粒体动力学基因的突变导致明显的阶段特异性缺陷，提供了生物学 该系统可以破译需要线粒体动力学的多种途径。要了解 如何维持 OXPHOS 复合物的质量，人类细胞中的创新基因筛选将 可用于识别感知和降解过量亚基的途径。这样的质量控制机制 与寿命调节有关。总而言之，这些方法将提供深入的 了解维持线粒体健康的稳态机制。