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Molecular Mechanism of Mitochondrial Membrane Transport

线粒体膜运输的分子机制

基本信息

批准号：
10034915
负责人：
Liang Feng
金额：
$ 43.95万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10034915
关键词：
Address Adopted Affinity Allosteric Regulation Apoptosis Architecture Binding Binding Sites Biophysics Calcium Calorimetry Cations Cell Death Cell Survival Cells Complex Cryoelectron Microscopy Crystallization Disease Epilepsy Future Gatekeeping Heart failure Homeostasis Homologous Gene Human Ion Channel Ions Link Mediating Metabolic Methods Mitochondria Molecular Molecular Probes Muscular Dystrophies Mutation N-terminal Neurodegenerative Disorders Neurons Pathology Physiological Physiological Processes Physiology Play Post-Translational Protein Processing Process Production Property Protein Isoforms Proteins Regulation Reperfusion Injury Resolution Rest Role Route Ruthenium Red Shapes Signal Transduction Structure Therapeutic Time Tissues Titrations Transmembrane Transport Work base calcium uniporter cell growth design excitotoxicity experimental study improved inhibitor/antagonist insight mitochondrial membrane novel novel therapeutics prevent response therapeutic target uptake

项目摘要

PROJECT SUMMARY Mitochondrial calcium (Ca2+) uptake is central to many fundamental physiological processes. It stimulates ATP production during times of increased metabolic need and provides a Ca2+ sink to modulate Ca2+-mediated signaling locally within a cell. Mitochondrial Ca2+ concentrations also regulate apoptosis and dysregulation–– specifically, Ca2+ overload––is a hallmark of pathologies ranging from neuronal excitotoxicity to heart failure and some epilepsies to muscular dystrophies. Yet despite the importance of mitochondrial Ca2+ uptake in normal physiology and disease, the molecular machinery mediating this process is relatively recently identified and many fundamental questions remain to be answered. The main route of Ca2+ influx to mitochondria is a channel called mitochondrial calcium uniporter, which includes the ubiquitous pore-forming subunit MCU and, depending on the species, several regulatory subunits (termed “uniplex” when in complex). This novel channel is highly selective for Ca2+, and its activity is tightly regulated by cytosolic Ca2+ concentration. My group recently determined a high-resolution crystal structure for a fungal MCU that defined a novel channel architecture and revealed a high-affinity Ca2+-binding site. Moreover, our cryo-EM structure of the human uniplex holocomplex revealed its architecture and hints at the mechanisms by which it is regulated. With these structures and the methods we developed, my lab is uniquely poised to embark on the mechanistic understanding of the mitochondrial calcium uniporter. Here, we propose to: 1) elucidate the structural and biophysical basis of ion selectivity, conduction and inhibition; 2) understand mechanisms of the channel gating and the long-range modulation; and 3) probe the molecular basis of Ca2+-dependent regulation of the uniplex. These results will give us much needed mechanistic insights into the activity and regulation of mitochondrial calcium uniporter, expanding our understanding of general principles of Ca2+ channels. In addition, they should provide a strong framework to aid the design of MCU inhibitors, which may represent promising treatments for diseases and pathologies marked by MCU dysregulation and mitochondrial Ca2+ overload. !

项目总结