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
基本信息
- 批准号:10405718
- 负责人:
- 金额:$ 79.44万
- 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 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAcuteAddressAerobicAffectAnaerobic BacteriaBiochemicalBiologyCalciumCell physiologyCellsCharcot-Marie-Tooth DiseaseComplexCytoskeletonCytosolDependenceDiseaseEndoplasmic ReticulumFMNL1 geneFilamentFilopodiaFocal Segmental GlomerulosclerosisGlycolysisGoalsGrantHealthHumanHypoxiaLinkMammalian CellMembrane LipidsMetabolicMetabolismMitochondriaModelingMutationMyosin Type IINatureNeuronsOrganellesParkinPathway interactionsPharmacologyPolymersProcessProtein KinaseProtein Kinase CProteinsProteomicsResearchRespirationSTK11 geneStress FibersStructureWorkactin 2basefascinfrontierlive cell microscopypolymerizationreconstitutionrecruit
项目摘要
The ‘actin cytoskeleton’ is not one structure but a number of distinct structures assembled and disassembled for
different purposes. In mammalian cells, a few abundant and easily recognizable structures dominate our view
of the actin cytoskeleton, including: stress fibers, lamellipodia and filopodia. However, a growing number of less
abundant and/or highly transient actin-based structures have been revealed, controlling important cellular
processes. Two such actin structures are the subject of this application: 1) CIA, calcium-induced actin; and 2)
ADA, acute depolarization-induced actin. Though highly transient, both structures are extensive in the cytosol
and affect important processes. In addition, both CIA and ADA impact the structure and function of mitochondria.
CIA depends on calcium activation of the formin protein INF2, which stimulates actin polymerization on the
endoplasmic reticulum and throughout the cytosol. Downstream effects of CIA include increased mitochondrial
calcium and increased mitochondrial fission. The importance of CIA is illustrated by the fact that INF2 mutations
link to two diseases, focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth disease (CMTD).
ADA is triggered by mitochondrial depolarization (either pharmacologically-induced or hypoxia-induced), which
activates two parallel pathways: 1) mitochondrial calcium release activates protein kinase C-, activating in turn
Rac, WAVE complex, and Arp2/3 complex; and 2) decreased ATP activates AMP-dependent protein kinase
(AMPK) through LKB1, activating in turn Cdc42 and FMNL formins. The ADA actin network is tightly associated
with mitochondria. An exciting new result is that one immediate consequence of ADA is rapid stimulation of
glycolysis. Additionally, ADA temporarily inhibits longer-term consequences of mitochondrial depolarization such
as mitochondrial reorganization and recruitment of the mitophagy protein Parkin. The goals in this grant period
are to elucidate both the mechanisms triggering CIA and ADA, as well as their downstream effects. These goals
will be accomplished using a combination of cellular approaches (live-cell microscopy, proteomics, metabolic
analysis) and biochemical approaches (cell-free reconstitution, analysis of purified proteins on model lipid
membranes). The questions to be asked include the following. 1) How is INF2 activated by increased calcium?
2) How are INF2-polymerized filaments organized into a network by myosin II and fascin? 3) How does CIA
interface with known mitochondrial fission proteins such as Mff and Drp1 to stimulate fission? 4) How do PKC
and AMPK activate Rac and Cdc42, respectively, during ADA? 5) How do Arp2/3 complex and FMNL formins
work together during ADA? 6) How does ADA stimulate glycolysis? These questions address fundamental
mechanistic questions important to a wide range of mammalian cells, and occupy an exciting frontier between
cytoskeletal biology, mitochondrial biology, and metabolism.
1
“肌动蛋白细胞骨架”不是一个结构,而是许多不同的结构组装和拆卸,
不同的目的在哺乳动物细胞中,一些丰富且易于识别的结构占据了我们的视野
肌动蛋白细胞骨架的结构,包括:应力纤维,板状伪足和丝状伪足。然而,越来越多的
已经揭示了丰富的和/或高度瞬时的肌动蛋白基结构,控制着重要的细胞
流程.两种这样的肌动蛋白结构是本申请的主题:1)CIA,钙诱导的肌动蛋白;和2)
ADA,急性去极化诱导肌动蛋白。虽然高度短暂,但这两种结构在细胞质中都广泛存在
并影响重要的过程。此外,CIA和ADA都影响线粒体的结构和功能。
CIA依赖于钙激活的α蛋白INF 2,它刺激肌动蛋白聚合在细胞膜上。
内质网和整个胞质溶胶。CIA的下游影响包括增加线粒体
钙和线粒体分裂增加。CIA的重要性是由INF 2突变的事实说明,
与两种疾病有关,即局灶节段性肾小球硬化症(FSGS)和腓骨肌萎缩症(CMTD)。
ADA由线粒体去极化(药理学诱导或缺氧诱导)触发,
激活两条平行的途径:1)线粒体钙释放激活蛋白激酶C-κ B,依次激活
Rac、WAVE复合物和Arp 2/3复合物; 2)ATP减少激活AMP依赖性蛋白激酶
(AMPK)通过LKB 1,依次激活Cdc 42和FMNL formins。ADA肌动蛋白网络与
与线粒体。一个令人兴奋的新结果是,ADA的一个直接后果是快速刺激
糖酵解此外,ADA暂时抑制线粒体去极化的长期后果,
作为线粒体重组和线粒体吞噬蛋白帕金的募集。本资助期的目标
旨在阐明触发CIA和ADA的机制及其下游效应。这些目标
将使用细胞方法(活细胞显微镜,蛋白质组学,代谢
分析)和生物化学方法(无细胞重建,在模型脂质上分析纯化的蛋白质
膜)。要问的问题包括以下几个方面。1)INF 2是如何通过增加钙激活的?
2)肌球蛋白II和肌成束蛋白是如何将INF 2聚合的纤维组织成网络的?3)中情局是怎么
与已知的线粒体分裂蛋白如Mff和Drp 1的接口来刺激分裂?4)PKC如何
和AMPK激活Rac和Cdc 42,分别在ADA?5)Arp 2/3复合物和FMNL是如何形成蛋白的
在ADA期间一起工作6)ADA如何刺激糖酵解?这些问题涉及基本的
机械问题的重要性,广泛的哺乳动物细胞,并占据了令人兴奋的前沿之间
细胞骨架生物学、线粒体生物学和代谢。
1
项目成果
期刊论文数量(0)
专著数量(0)
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
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:
$ 79.44万 - 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:
$ 79.44万 - 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:
$ 79.44万 - 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:
$ 79.44万 - 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:
$ 79.44万 - 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:
$ 79.44万 - 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:
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