Regulated Mitochondrial Morphology

调控线粒体形态

基本信息

批准号：
10248380
负责人：
David Bulkley
金额：
$ 31.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248380
关键词：
Acute Affect Aging Animal Model Automobile Driving Back Binding Sites Biochemical Cell Death Cell physiology Cells Chemicals Chronic Clinical Cryoelectron Microscopy Defect Disease Dynamin Dynamin 2 Endocytosis Equilibrium Family Filament GTP Binding Generations Genome Goals Guanine Nucleotides Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Higher Order Chromatin Structure Immune response Infection Injury Learning Length Literature Malignant Neoplasms Mechanics Membrane Metabolic Metabolism Mitochondria Modeling Modification Molecular Molecular Conformation Morphology Motion Mutation Myocardial Infarction Names Nerve Degeneration Nucleotides Organelles Outer Mitochondrial Membrane Pathway interactions Phosphorylation Play Polymers Positioning Attribute Post-Translational Protein Processing Production Property Proteins Reagent Regulation Research Activity Resolution Reticulum Role Signal Transduction Stroke Structure Surface Testing Therapeutic Tissues Toxic effect Ubiquitin Work base constriction copolymer dimer experimental study gain of function human disease inhibitor/antagonist injured insight interest novel novel therapeutics paralogous gene peroxisome proteostasis receptor receptor binding reconstitution recruit respiratory response to injury stressor tool

项目摘要

Abstract Regulated Mitochondrial Morphology The mitochondrial reticulum performs an astonishing number of essential cellular functions, including respiratory energy production, anabolic production of critical metabolites, and regulated cell death. Mutations, injuries, and infections degrade mitochondrial activity; and damaged or dysfunctional mitochondria are increasingly recognized as contributing if not causative factors for a long and still growing list of diseases. The most commonly observed defect seen in aging, injured, or diseased cells is a breakdown of the inter-connected reticulum into hyper-fragmented organelle units that lose their chemical potential and the integrity of their genomes. The observation of hyper-fission in disease settings generated clinical interest in specific inhibitors of the mitochondrial fission machinery to ameliorate a range of illness: from chronic neurodegeneration and certain cancers to more acute injuries like heart attack and stroke—with promising proof-of-concept studies in animal models. Progress has been slow, however, in part because we do not understand the molecular mechanisms that govern mitochondrial fission. Recent biochemical breakthroughs in our lab—in combination with the resolution revolution in electron cryo-microscopy or cryoEM—have finally prepared us to resolve the mechanisms that drive these fission machines in unprecedented detail. We propose to determine the structural mechanisms that govern recruitment and assembly of the fission machine on the surface of mitochondria through the activity of specialized receptors (Aim1). We further propose to determine the allosteric protein motions that harness the chemical energy present in guanine nucleotides to perform mechanical, constricting work on mitochondrial tubules (Aim 2). Finally, we propose to determine how post-translational modifications—including phosphorylation and SUMOylation—tune or turn off the activity of the fission machinery (Aim 3). Together, accomplishing these objectives will provide new and unique insights into how these fundamental cellular machines work and will enable a new generation of structure-guided studies to identify and characterize novel therapeutic opportunities.

抽象的调控线粒体形态线粒体网执行数量惊人的基本细胞功能，包括呼吸能量的产生、关键代谢物的合成代谢产生以及调节细胞死亡。突变、损伤和感染会降低线粒体活性并受损或功能失调；人们越来越认识到，线粒体在很长一段时间内即使不是致病因素，也是有贡献的。衰老、损伤或患病细胞中最常见的缺陷越来越多。是相互连接的网状体分解成高度破碎的细胞器单元，这些细胞器单元失去了它们的功能化学势及其基因组的完整性观察疾病中的超裂变。设置引起了对线粒体裂变机制的特定抑制剂的临床兴趣改善一系列疾病：从慢性神经退行性疾病和某些癌症到更急性的癌症心脏病和中风等损伤——在动物模型中进行了有希望的概念验证研究。然而，进展缓慢，部分原因是我们不了解其分子机制我们实验室最近取得的生化突破与控制线粒体裂变相结合。电子冷冻显微镜或冷冻电镜的分辨率革命——最终让我们做好了解决问题的准备我们建议以前所未有的细节确定驱动这些裂变机器的机制。控制裂变机在地表的招募和组装的结构机制我们进一步建议确定线粒体通过专门受体的活性。利用鸟嘌呤核苷酸中存在的化学能的变构蛋白运动对线粒体小管进行机械收缩工作（目标 2）。确定翻译后修饰（包括磷酸化和 SUMOylation）如何调节或关闭裂变机制的活动（目标 3），共同实现这些目标。提供关于这些基本细胞机器如何工作的新的、独特的见解，并将使新一代结构引导研究，以确定和表征新的治疗机会。