Structure, Turnover and Safeguard of Mitochondria

线粒体的结构、周转和保护

• 批准号: 10543492
• 负责人: Hiromi Sesaki
• 金额: $ 58.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543492
• 关键词: Biology; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Cells; Charcot-Marie-Tooth Disease; Complex; Contracts; Defect; Disease; Dynamin; Endoplasmic Reticulum; Equilibrium; Event; Evolution; Feedback; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Health; Human; Immune; Intervention; Label; Laboratories; Life; Link; Logic; Mediating; Membrane; Membrane Fusion; Metabolic syndrome; Mitochondria; Mitochondrial Proteins; Molecular; Monitor; Mus; Mutate; Nerve Degeneration; Neurodevelopmental Disorder; Neuronal Differentiation; Neuropathy; OPA1 gene; Optic Atrophy; Organelles; PINK1 gene; Parkin; Pathogenesis; Pathway interactions; Phase; Physiological; Proteins; Reaction; Regulation; Role; Shapes; Site; Structure; Translating; Ubiquitination; Work; age related neurodegeneration; biological adaptation to stress; experimental study; human disease; in vivo; insight; response; stem cells; ubiquitin ligase

Summary Mitochondria are essential organelles that control the life and death of cells. Mitochondria are highly dynamic: They grow, divide, and fuse, and when they eventually become damaged, undergo degradation Mitochondrial division is mediated by a dynamin-related GTPase, DRP1, while fusion is mediated by two dynamin-related GTPases, OPA1 and mitofusin. These GTPases are mutated in human diseases, including neurodevelopmental disorder, Charcot-Marie-Tooth neuropathy, and optic atrophy. Altered activities of these proteins have also been linked to metabolic syndrome, cardiovascular disease, and age-related neurodegeneration. My laboratory’s goal is to decipher the molecular mechanisms that control mitochondrial structure and translate the fundamental biology to disease interventions. In the past two decades, we have identified and characterized the three essential GTPases in the core reactions of membrane fusion and division. The roles of mitochondrial dynamics are ever-expanding, and now include size control of mitochondria, their distribution and turnover, and differentiation of neurons, cardiomyocytes, stem cells, and immune cells. Most recently, it became evident that the mechanisms of mitochondrial division and fusion are much more complex than initially imagined, involving inter-organelle interactions and a feedback response that monitors and tunes their balance. The emerging new biology is transforming the field of mitochondrial structure and dynamics. In the next 5 years, we will address the important questions raised by this intellectual evolution. First, to our surprise, we found that DRP1 shapes the endoplasmic reticulum (ER) into tubules that form contract sites with mitochondria. DRP1-produced ER-mitochondria contact sites strongly promote mitochondrial division. We will investigate how DRP1 creates ER-mitochondria contact sites that specifically function in mitochondrial division, associates with the ER, and deforms the ER membrane. Second, we discovered a physiological pathway of mitochondrial turnover via DRP1-controlled, Parkin/PINK1- independent mitophagy in mice. This pathway’s most upstream event is to recognize and mark damaged mitochondria by ubiquitination of mitochondrial proteins. Our initial experiments suggested that ubiquitination occurs in two phases – reversible initiation and committed amplification. We will determine what ubiquitinates mitochondria in each phase, and how the ubiquitin ligase complexes recognize and label damaged mitochondria in vivo. Third, we found the first example of a stress response (MitoSafe) that senses and adjusts the mitochondrial structure by controlling the balance between fusion and division. We will explore the molecular basis of MitoSafe and its physiological roles in mice. The MIRA grant will enable us to discover the new logics of mitochondrial structure and its physiological role and regulation in vivo.

概括 线粒体是控制细胞生命和死亡的重要细胞器。线粒体高度 动态：它们成长，分裂和保险丝，当它们有时被损坏时，会降解 线粒体分裂由Dynamin相关的GTPase DRP1介导，而融合由两个介导 动力蛋白相关的GTPases，OPA1和丝线表示。这些GTPases在人类疾病中被突变，包括 神经发育障碍，charcot-marie-tooth神经病和视神经萎缩。这些活动的改变 蛋白质也与代谢综合征，心血管疾病和与年龄有关的蛋白质有关 神经变性。我的实验室的目标是破译控制线粒体的分子机制 结构并将基本生物学转化为疾病干预措施。在过去的二十年中，我们有 在膜融合的核心反应和 分配。线粒体动力学的作用一直在扩展，现在包括 线粒体，其分布和周转率以及神经元，心肌细胞，干细胞和 免疫细胞。最近，有证据表明线粒体分裂和融合的机制是 比最初想象的要复杂得多，涉及轨道间的相互作用和反馈响应 监视并调整其平衡。新兴的新生物学正在改变线粒体结构的领域 和动态。在接下来的5年中，我们将解决这种智力进化提出的重要问题。 首先，令我们惊讶的是，我们发现DRP1将内质网（ER）塑造成形成的小管 与线粒体合同。 DRP1生产的ER - 原则接触位点强烈促进 线粒体部门。我们将调查DRP1如何创建ER-Mochondria接触站点 特别是在线粒体分裂中，与ER相关，并变形了ER膜。 其次，我们通过DRP1控制，Parkin/Pink1-发现了线粒体周转的物理途径 小鼠独立线索。该途径最上游的事件是识别和标记损坏 线粒体蛋白质的泛素化。我们的最初实验表明泛素化 出现在两个阶段 - 可逆计划和承诺放大。我们将确定什么 在每个阶段的泛素线粒体，以及泛素连接酶络合物如何识别和标记 体内线粒体受损。第三，我们发现了感官的应力反应（Mitosafe）的第一个例子 并通过控制融合和分裂之间的平衡来调整线粒体结构。我们将 探索Mitosafe的分子基础及其在小鼠中的物理作用。 Mira Grant将启用 我们发现线粒体结构的新逻辑及其在体内的身体作用和调节。