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
- 来源:
- 关键词:ActinsAdhesionsAlzheimer&aposs DiseaseAwardBiochemicalCalciumCell physiologyCellsCellular biologyCharcot-Marie-Tooth DiseaseCytoskeletonDefectDiseaseDynaminEndoplasmic ReticulumEventFamilyFilopodiaFocal Segmental GlomerulosclerosisGoalsGuanosine Triphosphate PhosphohydrolasesHomeostasisHuntington DiseaseIonophoresKidney DiseasesKnowledgeLaboratoriesLinkMammalsMediatingMembraneMetabolicMicrofilamentsMitochondriaMutationNeurodegenerative DisordersOrganellesOxidative StressParentsParkinson DiseasePathologyPeripheral Nervous System DiseasesPhysiologicalPlayPopulationProcessProteinsResearchRoleSignal TransductionSiteStimulusSystemVisionWorkbasebiological adaptation to stressconstrictionhuman diseaseimaging systeminterestnovelpolymerizationreconstitutionrecruittemporal measurement
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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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:
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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