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Fis1 Regulation of Mitochondrial Fission

Fis1 线粒体裂变的调节

基本信息

批准号：
9762503
负责人：
R Blake Hill
金额：
$ 36.53万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762503
关键词：
Ablation Aging Alzheimer&apos s Disease Apoptosis Autophagosome Binding Biochemical Biological Cell Culture Techniques Cells Cellular Structures Cessation of life Complement Complex Cytology Data Daughter Diabetes Mellitus Dimerization Disease Dynamin Dynamin I Elements Enzymes Eukaryota Event Excision Failure Future GTPase-Activating Proteins Gaussian model Genetic Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Heart Diseases Human Human Biology Hydrolysis Impairment In Vitro Kinetics Lead Life Life Cycle Stages Liposomes Malignant Neoplasms Mammals Measures Mediating Membrane Microscopic Mitochondria Mitochondrial Proteins Modeling Morphology Mutation NMR Spectroscopy Neonatal Neurodegenerative Disorders Neurons Organelles Outcome Parkinson Disease Power Plants Process Protein Isoforms Proteins Quality Control RNA Splicing Recombinants Regulation Roentgen Rays Role Saccharomycetales Schizosaccharomyces pombe Proteins Site Stress Structure Synchrotrons Syndrome Testing Transmembrane Domain Variant Work X-Ray Crystallography Yeasts cell type dimer genetic approach human disease inhibitor/antagonist insight live cell microscopy mimetics mutant novel therapeutic intervention overexpression protein protein interaction reconstitution recruit scaffold small molecule tool

项目摘要

Project Summary/Abstract Altered division, or fission, of mitochondria has severe consequences even death. Yet the reasons for this are unknown. It is postulated that the mitochondria have their own lifecycle that involves fission of unhealthy mitochondria to remove them in an autophagic process called mitophagy. These quality control processes are evolutionarily conserved between budding yeast and humans, although extent to which has recently been called into question. In yeast, fission requires the protein FIS1 that is now thought to be dispensable for fission in mammals, but indispensable for mitophagy. Consistent with this view are FIS1 interactions in mitophagy human cell culture. Contrary to this view, loss of FIS1 elongates mitochondrial and displaces the fission mechanoenzyme DRP1 from mitochondria in some, but not all, cell types. Mutations to some evolutionarily conserved residues in FIS1 impair fission and DRP1 localization. Mutations to different conserved residues impair binding to a critical adaptor in mitophagy, the Rab7 GTPase Activating Proteins TBC1D15 and TBC1D17. These findings suggest that FIS1 is conserved for roles in both fission and mitophagy. Using yeast- inspired mutations, along with state-of-the-art genetic, microscopic, and structural tools, we are now poised to determine how conserved components govern the fate of mitochondria between fission, mitophagy, or apoptosis. To understand the protein-protein interactions that govern this, biochemical and structural studies will be integrated with state-of-the-art cell biological and genetic approaches. A better understanding of the protein machinery and how it works will identify key points of regulation that may be targeted in future studies with small molecules to inhibitor, and activate fission, mitophagy, and apoptosis. The discovery of such molecules may ultimately lead to treatments for diseases in which enhanced, or impaired, fission activity is central.

项目总结/摘要线粒体分裂或分裂的改变会导致严重后果，甚至死亡。然而，是未知的。据推测，线粒体有自己的生命周期，涉及裂变的不健康的线粒体在自噬过程中将其去除，称为线粒体自噬。这些质量控制过程是在芽殖酵母和人类之间进化上保守，尽管最近在某种程度上已经被发现。受到质疑在酵母中，裂变需要FIS 1蛋白质，现在认为FIS 1蛋白质是裂变的关键在哺乳动物中，但对线粒体自噬是必不可少的。与此观点一致的是FIS 1在线粒体自噬中的相互作用人类细胞培养与这种观点相反，FIS 1的缺失延长了线粒体并取代了核分裂。机械酶DRP 1从线粒体在一些，但不是所有的细胞类型。一些进化上的突变 FIS 1中的保守残基损害分裂和DRP 1定位。不同保守残基的突变削弱与线粒体自噬中的关键衔接子Rab 7 GT3活化蛋白TBC 1D 15的结合， TBC1D17。这些发现表明FIS 1在分裂和线粒体自噬中的作用是保守的。使用酵母- 灵感突变，沿着最先进的遗传，微观和结构工具，我们现在准备确定保守的成分如何控制线粒体在分裂，线粒体自噬，凋亡为了了解蛋白质之间的相互作用，生物化学和结构研究将与最先进的细胞生物学和遗传学方法相结合。更好地理解蛋白质机制及其工作原理将确定未来研究可能针对的关键调控点与小分子抑制剂，并激活裂变，线粒体自噬和凋亡。通知发现分子可能最终导致对疾病的治疗，其中增强或受损的裂变活性是中环