Molecular Mechanisms of Mitochondrial Biogenesis

线粒体生物发生的分子机制

基本信息

批准号：
10735778
负责人：
Eunyong Park
金额：
$ 31.87万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735778
关键词：
ATP phosphohydrolase Address Aging Apoptosis Architecture Area Binding Biochemical Biogenesis Biology Cardiovascular Diseases Cells Client Complex Couples Cryoelectron Microscopy Cytosol Data Defect Disease Genome Goals Homeostasis Human Innate Immune Response Inner mitochondrial membrane Integral Membrane Protein Maintenance Manuscripts Mediating Membrane Metabolic syndrome Metabolism Mitochondria Mitochondrial Proteins Molecular Molecular Conformation Molecular Machines Multiprotein Complexes Nerve Degeneration Neurodegenerative Disorders Nuclear Organelles Outcome Study Outer Mitochondrial Membrane Oxidative Phosphorylation PINK1 gene Pathogenesis Pathway interactions Permeability Phosphotransferases Physiology Play Process Protein Biosynthesis Protein Import Protein Inhibition Protein Precursors Protein translocation Proteins Publishing Quality Control Research Resolution Respiration Rest Ribosomes Role Saccharomyces cerevisiae Signal Transduction Sorting Structure Testing Therapeutic Intervention Thinness Visualization Water biophysical analysis biophysical techniques driving force human disease insight mitochondrial dysfunction molecular dynamics novel strategies polypeptide small molecule therapeutically effective translocase

项目摘要

PROJECT SUMMARY Mitochondria are endosymbiotically-derived double membrane-bound organelles which provide cells with energy via oxidative respiration. Mitochondria also serve as a major hub for cellular metabolism and are involved in numerous vital pathways, including cell signaling, innate immune response, and apoptosis. Dysfunction of mitochondria is implicated in aging and many diseases and is a potential causative factor in neurodegenerative diseases. Most of >1,000 mitochondrial proteins are encoded by the nuclear genome and thus are imported from the cytosol shortly after being synthesized as precursors on cytosolic ribosomes. Thus, mitochondrial protein import is an essential process required for biogenesis and functional maintenance of mitochondria. The import process is mainly mediated by two universally conserved membrane complexes, the translocase of the outer membrane (TOM) complex and the translocase of the inner membrane (TIM) complex. The TOM complex mediates the initial translocation of precursor proteins across the outer mitochondrial membrane, and the TIM complex further translocates the precursor proteins across the inner mitochondrial membrane. The TIM complex is also responsible for integration of many integral membrane proteins to the inner membrane. Currently, it is poorly understood how the TOM and TIM complexes mediate these translocation processes. In the current proposal, we aim to address central outstanding questions about protein import mechanisms by the TOM and TIM complexes, using structural, biochemical, and biophysical approaches. These questions include how the translocase complexes specifically recognize their client proteins, how they form a path for protein translocation in the membranes, what are the molecular interactions and forces driving protein translocation, and how the translocase complexes are regulated. In particular, we will perform several cryo-electron microscopy (cryo-EM) studies to visualize the translocase complexes in different functional states, including substrate-engaged states, and gain insights into their mechanisms for substrate engagement and conformational changes. The outcomes of these studies will fundamentally advance our understanding of mitochondrial biology and provide new insights to develop novel approaches to treat mitochondrial-associated diseases, such as neurodegenerative diseases.

项目概要线粒体是内共生衍生的双膜结合细胞器，为细胞提供通过氧化呼吸获取能量。线粒体也是细胞代谢的主要枢纽，参与许多重要途径，包括细胞信号传导、先天免疫反应和细胞凋亡。线粒体功能障碍与衰老和许多疾病有关，并且是潜在的致病因素神经退行性疾病。超过 1,000 种线粒体蛋白中的大多数是由核基因组编码的因此在作为胞质核糖体上的前体合成后不久就从胞质中输入。因此，线粒体蛋白输入是生物发生和功能维持所需的重要过程线粒体。输入过程主要由两种普遍保守的膜复合物介导，即外膜转位酶 (TOM) 复合物和内膜转位酶 (TIM) 复合物。 TOM 复合物介导前体蛋白穿过线粒体外的初始易位 TIM 复合物进一步将前体蛋白跨过线粒体内部膜。 TIM 复合物还负责将许多整合膜蛋白整合到内膜。目前，人们对 TOM 和 TIM 复合物如何介导这些作用知之甚少。易位过程。在当前的提案中，我们的目标是解决以下核心悬而未决的问题：利用结构、生物化学和生物物理学研究 TOM 和 TIM 复合物的蛋白质输入机制接近。这些问题包括易位酶复合物如何特异性识别其客户蛋白质，它们如何形成膜中蛋白质易位的路径，分子相互作用是什么和驱动蛋白质易位的力量，以及易位酶复合物是如何调节的。特别是，我们将进行多项冷冻电子显微镜 (cryo-EM) 研究，以可视化不同环境下的转位酶复合物功能状态，包括底物接合状态，并深入了解其底物机制参与和构象变化。这些研究的结果将从根本上推进我们的了解线粒体生物学并为开发新的治疗方法提供新见解线粒体相关疾病，例如神经退行性疾病。