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

基本信息

  • 批准号:
    10004663
  • 负责人:
  • 金额:
    $ 76.19万
  • 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

We have a long-standing interest in actin polymerization mechanisms, which has led us to investigate quantitatively minor populations of filaments with important cellular roles. One such actin population functions in mitochondrial fission. Mitochondrial fission is required 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 focus on an endoplasmic reticulum-bound formin, INF2, which assembles this filament population. 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.
我们长期以来一直对肌动蛋白聚合机制感兴趣,这导致我们研究 数量很少的细丝种群,具有重要的细胞作用。一个这样的肌动蛋白群体 线粒体分裂的功能。线粒体的分裂是线粒体正常分布所必需的, 有丝分裂、氧化应激反应和对不同代谢底物的适应。中的缺陷 线粒体分裂与主要神经退行性疾病的病理有关,包括 阿尔茨海默氏症、亨廷顿氏症、帕金森氏症和肌萎缩侧索硬化症。Dynamin家族GTP酶Drp1是一个核心角色 在线粒体分裂中,分裂部位的寡聚和促进膜收缩。尽管如此, 引发线粒体分裂的机制尚不清楚。我们发现肌动蛋白聚合 At在哺乳动物的DRp1募集和线粒体分裂中起着重要的作用。这 这一发现来自我们对内质网结合的福尔马林INF2的关注,它组装了这种 灯丝种群。通过这些研究,我们开发了用于成像的活细胞系统 线粒体在高空间和时间分辨率下的分裂,这使得我们能够定义 导致线粒体上Drp1寡聚化的事件。我们还建立了精炼的 研究肌动蛋白与Drp1、INF2和其他裂变成分相互作用的生化系统 这一过程将最终实现无细胞的裂变重组。这些发现已经 从根本上改变了我们对线粒体裂变的看法。我们未来五年的目标是明确 一种详细的哺乳动物线粒体分裂(由钙离子载体刺激),以及 随后,利用这一知识来定义由其他刺激诱导的裂变机制。我们有 两个较长期的目标:使用纯化的成分重建肌动蛋白介导的线粒体分裂 (这将表明完全机械性的理解),并定义激活的信号输入 在特定的生理情况下发生的裂变。INF2基因突变与两名人类 疾病:局灶性和节段性肾小球硬化(一种肾脏疾病)和夏科-玛丽-牙病 疾病(一种外周神经病)。因此,我们的工作既影响基础细胞生物学,也影响疾病- 基础研究。实验室的第二个重点是通过福尔明FMNL3组装丝状伪足。而当 没有在本研究战略中讨论,我们将在本Mira中继续我们的丝状目录工作。类似于我们的 INF2研究,多年来仔细的细胞和生化研究导致了令人惊讶的发现, 包括1)丝状伪足与细胞-细胞和细胞-底物黏附之间的联系,以及2)在 FMNL3在内体动力学中的表达。我们的总体设想是有未被发现的肌动蛋白种群 细丝,瞬时的,低丰度的,调节关键的细胞功能。综合研究 在我的实验室里正在揭示这些肌动蛋白细丝群体。

项目成果

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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

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
  • 批准号:
    10387000
  • 财政年份:
    2017
  • 资助金额:
    $ 76.19万
  • 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:
    9276895
  • 财政年份:
    2017
  • 资助金额:
    $ 76.19万
  • 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:
    $ 76.19万
  • 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:
    $ 76.19万
  • 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:
    $ 76.19万
  • 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:
    $ 76.19万
  • 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:
    $ 76.19万
  • 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:
    $ 76.19万
  • 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:
    $ 76.19万
  • 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:
    $ 76.19万
  • 项目类别:

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