权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Determining the mechanism of mitochondrial outer membrane fusion

确定线粒体外膜融合的机制

基本信息

批准号：
10619656
负责人：
Suzanne C Hoppins
金额：
$ 32.03万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2017-02-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619656
关键词：
Address Aging Allosteric Regulation Apoptotic Ataxia Automobile Driving Behavior Binding Binding Proteins Biochemical Biochemistry Biological Assay Biology Cell physiology Cells Cellular biology Collection Compensation Complement Complex Cytoplasmic Protein Cytosol Data Defect Development Disease Dynamin Event Family Fluorescence Resonance Energy Transfer GTP Binding Genes Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Homology Modeling Hydrolysis Impairment Knowledge Link Maps Mediating Membrane Membrane Fusion Metabolic Microtubules Mitochondria Modeling Molecular Molecular Conformation Movement Muscle Mutation Myopathy Nerve Degeneration Neurodegenerative Disorders Neurons Optic Atrophy Organelles Outer Mitochondrial Membrane Pathway interactions Patients Peripheral Nervous System Diseases Polymers Positioning Attribute Production Property Protein Dynamics Proteins Publishing Regulation Research Shapes Stimulus Stress Structure Techniques Testing Transmembrane Domain Tubulin Variant Work age related experimental study flexibility insight mitochondrial dysfunction novel novel strategies paralogous gene pro-apoptotic protein programs reconstitution self assembly therapeutic development tool

项目摘要

Project Summary This proposal examines the mitofusin proteins, which catalyze both mitochondrial tethering and outer membrane fusion. Mitochondrial shape is central to mitochondrial function and is closely linked to changes in cellular physiology during development, stress, and aging. Mitochondrial fusion increases metabolic production, protects against excessive degradation of mitochondria, reduces sensitivity of the cell to apoptotic stimuli and allows functional complementation of damaged organelles. Compromised mitochondrial function and decreased organelle connectivity are associated with neurodegeneration and other age-related diseases. Furthermore, mutations in the genes encoding components of the mitochondrial fusion machine cause peripheral neuropathy, optic atrophy, myopathy and ataxia. Both mitochondrial division and mitochondrial fusion are mediated by conserved dynamin superfamily proteins. This diverse family of mechanochemical GTPases couple self-assembly and conformational changes to membrane remodeling events throughout the cell. Mitofusin is the mitochondrial outer membrane fusion machine and must assemble both in cis within a single membrane, and in trans across two mitochondria. The molecular details, including of the composition of these assemblies, the regulation of their formation and how they contribute to membrane tethering and fusion are not known. We address these gaps in knowledge utilizing biochemical analyses of mitofusin function. In Aim 1, we will elucidate mechanisms of allosteric regulation that control assembly of mitofusin into fusion- competent complexes. Our collection of functional variants and novel approaches will provide a powerful tool in dissecting the contribution of each mitofusin functional domain to cis oligomerization and trans complex formation. Our work characterizing CMT2A-associated variants of mitofusin revealed that molecular defects of mitofusin can be compensated for by cytosolic factors in cells. In Aim 2, we use a reductionist approach that combines cell biology, biochemistry, and reconstituted assays developed in my lab to determine how the cytosolic mitofusin effectors Bax and MSTO1 alter mitofusin assembly to regulate mitochondrial fusion. This research program draws on our strengths in cellular and biochemical analysis of mitochondrial biology and will yield fundamental insights not only for mitochondrial dynamics but for the mechanisms through which dynamin superfamily proteins in general operate.

项目总结