Structure, Turnover and Safeguard of Mitochondria

线粒体的结构、周转和保护

基本信息

  • 批准号:
    10330706
  • 负责人:
  • 金额:
    $ 34.07万
  • 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

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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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:
    10543492
  • 财政年份:
    2022
  • 资助金额:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 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:
    $ 34.07万
  • 项目类别:

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