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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：
HENRY N HIGGS
金额：
$ 5.34万
依托单位：
DARTMOUTH COLLEGE
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：
https://reporter.nih.gov/project-details/10387000
关键词：
Actins Adhesions Alzheimer&apos s Disease Award Biochemical Calcium Cell physiology Cells Cellular biology Charcot-Marie-Tooth Disease Cytoskeleton Defect Disease Dynamin Endoplasmic Reticulum Event Family Filopodia Focal Segmental Glomerulosclerosis Goals Guanosine Triphosphate Phosphohydrolases Homeostasis Huntington Disease Ionophores Kidney Diseases Knowledge Laboratories Link Mammals Mediating Membrane Metabolic Microfilaments Mitochondria Mutation Neurodegenerative Disorders Organelles Oxidative Stress Parents Parkinson Disease Pathology Peripheral Nervous System Diseases Physiological Play Population Process Proteins Research Role Signal Transduction Site Stimulus System Vision Work base biological adaptation to stress constriction human disease imaging system interest novel polymerization reconstitution recruit temporal 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