Structure, Turnover and Safeguard of Mitochondria

线粒体的结构、周转和保护

• 批准号: 10581869
• 负责人: Hiromi Sesaki
• 金额: $ 3.99万
• 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/10581869
• 关键词: Address; 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; Neurons; 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， 通过Dynamin相关的GTPase DRP1，DRP1，DRP1，进行降解线粒体分裂介导 融合是由两个与动力学相关的GTPases OPA1和丝线表示介导的。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。这些蛋白质的活性改变也已经 与代谢综合征，心血管疾病和与年龄相关的神经变性有关。我的 实验室的目标是破译控制线粒体结构的分子机制 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 已经确定并表征了三个基本GTPases的核心反应 膜融合和分裂。线粒体动力学的作用不断扩大，并且 现在包括线粒体的尺寸控制，它们的分布和周转率以及分化 神经元，心肌细胞，干细胞和免疫细胞。最近，这证明了 线粒体划分和融合的机制比最初要复杂得多 想象中的，涉及轨道间相互作用以及监视和 调整他们的平衡。新兴的新生物学正在改变线粒体领域 结构和动态。在接下来的5年中，我们将解决由 这种智力进化。 首先，令我们惊讶的是，我们发现DRP1将内质网（ER）塑造成 与线粒体形成合同部位的小管。 DRP1生产的ER-线粒体接触 站点强烈促进线粒体分裂。我们将研究DRP1如何创建ER- 线粒体接触位点在线粒体划分中专门起作用 与ER一起变形ER膜。其次，我们发现了一条物理路径 通过DRP1控制的，parkin/pink1无关的线粒体的线粒体转换。 该途径最上游的活动是识别并标记损坏的线粒体 线粒体蛋白的泛素化。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 哪些泛素在每个阶段都在线粒体上以及泛素连接酶配合物如何 在体内公认并标记了线粒体损坏。第三，我们找到了一个的第一个例子 应力反应（Mitosafe）通过控制线粒体结构并调节线粒体结构 融合与分裂之间的平衡。我们将探索Mitosafe的分子基础 及其在小鼠中的身体角色。 Mira Grant将使我们能够发现新的逻辑 线粒体结构及其体内的身体作用和调节。