Supplement - Linking actin cytoskeleton to membrane dynamics in mitochondrial fission

补充-将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来

基本信息

  • 批准号:
    10387000
  • 负责人:
  • 金额:
    $ 5.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

Abstract of Parent Award Mitochondrial fission is essential for proper mitochondrial distribution, mitophagy, oxidative stress response, and adaptation to varying metabolic substrates. Defects in mitochondrial fission are linked to the pathology of major neurodegenerative diseases, including Alzheimer’s, Huntington’s, Parkinson’s, and ALS. The dynamin family GTPase Drp1 is a central player in mitochondrial fission, oligomerizing at fission sites and promoting membrane constriction. Still, the mechanisms that trigger mitochondrial fission are murky. We have discovered that actin polymerization at fission sites plays a major role in Drp1 recruitment and mitochondrial fission in mammals. This finding came from our long-term interest in actin polymerization through formin proteins, with particular focus on an endoplasmic reticulum-bound formin, INF2. Through these studies, we have developed live-cell systems for imaging mitochondrial fission at high spatial and temporal resolution, which have allowed us to define the order of events leading to Drp1 oligomerization on mitochondria. We have also established refined biochemical systems to study interaction of actin with Drp1, INF2 and other components of the fission process, which will enable eventual cell-free reconstitution of fission. These discoveries have fundamentally changed our view of mitochondrial fission. Our goal in the next five years is to define one “type” of mammalian mitochondrial fission in detail (stimulated by calcium ionophore), and subsequently to use this knowledge to define fission mechanisms induced by other stimuli. We have two longer-term goals: to reconstitute actin- mediated mitochondrial fission using purified components (which would indicate full mechanistic understanding), and to define the signaling in-puts that activate fission in specific physiological situations. Mutations in INF2 are causally linked to two human diseases: focal and segmental glomerulosclerosis (a kidney disease) and Charcot-Marie-Tooth disease (a peripheral neuropathy). Thus, our work impacts both fundamental cell biology and disease-based research. A second focus of the laboratory is filopodia assembly by the formin FMNL3. While not discussed in this Research Strategy, we will continue our filopodia work in this MIRA. Similar to our INF2 studies, years of careful cellular and biochemical work are leading to surprising discoveries, including 1) links between filopodia and both cell-cell and cell- substratum adhesion, and 2) a role for FMNL3 in endosomal dynamics. Our overall vision is that there are undiscovered populations of actin filaments, transient and of low abundance, which mediate key cellular functions. The combined studies in my laboratory are revealing these actin filament populations.
家长奖摘要

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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HENRY N HIGGS其他文献

HENRY N HIGGS的其他文献

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{{ truncateString('HENRY N HIGGS', 18)}}的其他基金

Linking actin cytoskeleton to membrane dynamics in mitochondrial fission
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来
  • 批准号:
    9276895
  • 财政年份:
    2017
  • 资助金额:
    $ 5.34万
  • 项目类别:
Linking actin cytoskeleton to membrane dynamics in mitochondrial fission
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来
  • 批准号:
    10004663
  • 财政年份:
    2017
  • 资助金额:
    $ 5.34万
  • 项目类别:
Linking actin cytoskeleton to membrane dynamics in mitochondrial fission - Undergrad Supplement
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来 - 本科生补充
  • 批准号:
    10591210
  • 财政年份:
    2017
  • 资助金额:
    $ 5.34万
  • 项目类别:
The impact of dynamic actin polymerization on mitochondrial dynamics and function
动态肌动蛋白聚合对线粒体动力学和功能的影响
  • 批准号:
    10405718
  • 财政年份:
    2017
  • 资助金额:
    $ 5.34万
  • 项目类别:
The impact of dynamic actin polymerization on mitochondrial dynamics and function
动态肌动蛋白聚合对线粒体动力学和功能的影响
  • 批准号:
    10670903
  • 财政年份:
    2017
  • 资助金额:
    $ 5.34万
  • 项目类别:
Linking actin cytoskeleton to membrane dynamics in mitochondrial fission
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来
  • 批准号:
    10245015
  • 财政年份:
    2017
  • 资助金额:
    $ 5.34万
  • 项目类别:
Molecular Interactions and Imaging Core
分子相互作用和成像核心
  • 批准号:
    10460274
  • 财政年份:
    2016
  • 资助金额:
    $ 5.34万
  • 项目类别:
Molecular Interactions and Imaging Core
分子相互作用和成像核心
  • 批准号:
    10647704
  • 财政年份:
    2016
  • 资助金额:
    $ 5.34万
  • 项目类别:
Molecular Interactions and Imaging Core
分子相互作用和成像核心
  • 批准号:
    10271748
  • 财政年份:
    2016
  • 资助金额:
    $ 5.34万
  • 项目类别:
Filopodia assembly by FMNL3: biochemical mechanism and cellular function
FMNL3 的丝状伪足组装:生化机制和细胞功能
  • 批准号:
    8669584
  • 财政年份:
    2015
  • 资助金额:
    $ 5.34万
  • 项目类别:

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