Structure, Turnover and Safeguard of Mitochondria

线粒体的结构、周转和保护

基本信息

  • 批准号:
    10543492
  • 负责人:
  • 金额:
    $ 58.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
总结 线粒体是控制细胞生死的重要细胞器。线粒体高度 动态:它们生长、分裂和融合,当它们最终受损时,就会退化。 线粒体分裂是由动力蛋白相关的GT3,DRP 1介导的,而融合是由两个 动力蛋白相关的GTP酶、OPA 1和线粒体融合蛋白。这些GTP酶在人类疾病中发生突变,包括 神经发育障碍、腓骨肌萎缩性神经病和视神经萎缩。这些活动的变化 蛋白质也与代谢综合征、心血管疾病和年龄相关的疾病有关。 神经变性我实验室的目标是破译控制线粒体的分子机制 构建并将基础生物学转化为疾病干预措施。在过去的二十年里, 鉴定并表征了膜融合核心反应中的三种必需GTP酶, 师.线粒体动力学的作用正在不断扩大,现在包括对线粒体大小的控制。 线粒体,它们的分布和周转,以及神经元、心肌细胞、干细胞和 免疫细胞最近,很明显,线粒体分裂和融合的机制是 比最初想象的要复杂得多,涉及细胞器间的相互作用和反馈反应, 监控并调整它们的平衡新兴的新生物学正在改变线粒体结构领域 和动态。在接下来的5年里,我们将解决这一知识演变所提出的重要问题。 首先,令我们惊讶的是,我们发现DRP 1将内质网(ER)塑造成小管, 与线粒体的接触点。DRP 1产生的ER-线粒体接触位点强烈促进 线粒体分裂我们将研究DRP 1如何创建ER-线粒体接触位点, 特异性地在线粒体分裂中起作用,与ER相关,并使ER膜变形。 其次,我们发现了通过MRP 1控制的Parkin/PINK 1-线粒体转换的生理途径 小鼠的独立线粒体自噬。这条通路的最上游事件是识别和标记受损的 线粒体蛋白的泛素化。我们最初的实验表明, 发生在两个阶段-可逆的启动和承诺的扩增。我们将决定 泛素化线粒体在每个阶段,以及泛素连接酶复合物如何识别和标记 体内线粒体受损。第三,我们发现了第一个压力反应(MitoSafe)的例子, 并通过控制融合和分裂之间的平衡来调节线粒体结构。我们将 探讨MitoSafe的分子基础及其在小鼠体内的生理作用。MIRA将使 从而揭示线粒体结构的新逻辑及其在体内的生理作用和调控。

项目成果

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Hiromi Sesaki其他文献

Hiromi Sesaki的其他文献

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{{ truncateString('Hiromi Sesaki', 18)}}的其他基金

Structure, Turnover and Safeguard of Mitochondria
线粒体的结构、周转和保护
  • 批准号:
    10330706
  • 财政年份:
    2022
  • 资助金额:
    $ 58.12万
  • 项目类别:
Structure, Turnover and Safeguard of Mitochondria
线粒体的结构、周转和保护
  • 批准号:
    10798515
  • 财政年份:
    2022
  • 资助金额:
    $ 58.12万
  • 项目类别:
Structure, Turnover and Safeguard of Mitochondria
线粒体的结构、周转和保护
  • 批准号:
    10581869
  • 财政年份:
    2022
  • 资助金额:
    $ 58.12万
  • 项目类别:
Regulation of Mitochondrial Division by Phosphatidic Acid
磷脂酸对线粒体分裂的调节
  • 批准号:
    10000939
  • 财政年份:
    2019
  • 资助金额:
    $ 58.12万
  • 项目类别:
Regulation of Mitochondrial Division by Phosphatidic Acid
磷脂酸对线粒体分裂的调节
  • 批准号:
    10241320
  • 财政年份:
    2019
  • 资助金额:
    $ 58.12万
  • 项目类别:
Mitochondrial Quality Control by Drp1
Drp1 的线粒体质量控制
  • 批准号:
    9929888
  • 财政年份:
    2018
  • 资助金额:
    $ 58.12万
  • 项目类别:
Mitochondrial Quality Control by Drp1
Drp1 的线粒体质量控制
  • 批准号:
    9889969
  • 财政年份:
    2018
  • 资助金额:
    $ 58.12万
  • 项目类别:
Introducing Mitochondrial Stasis in Neurons
在神经元中引入线粒体停滞
  • 批准号:
    8568892
  • 财政年份:
    2013
  • 资助金额:
    $ 58.12万
  • 项目类别:
Mitochondrial Fusion and Division
线粒体融合与分裂
  • 批准号:
    8270512
  • 财政年份:
    2010
  • 资助金额:
    $ 58.12万
  • 项目类别:
Mitochondrial Fusion and Division
线粒体融合与分裂
  • 批准号:
    7985893
  • 财政年份:
    2010
  • 资助金额:
    $ 58.12万
  • 项目类别:

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