Spatial Organization of the Mitochondrial Inner Membrane

线粒体内膜的空间组织

• 批准号: 10229557
• 负责人: Jonathan R. Friedman
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10229557
• 关键词: Address; Alzheimer' s Disease; Architecture; Cell Respiration; Cell physiology; Cells; Complex; Crista ampullaris; Defect; Development; Disease; Elements; Future; Generations; Goals; Homeostasis; Human; Inner mitochondrial membrane; Ions; Lead; Link; Membrane; Mitochondria; Molecular; Morphogenesis; Morphology; Neurodegenerative Disorders; Nucleotides; Organelles; Oxidative Phosphorylation; Parkinson Disease; Phenotype; Phospholipids; Positioning Attribute; Production; Research; Respiration; Role; Site; Structure; System; Therapeutic; Work; Yeasts; amino acid metabolism; genetic approach; human disease; insight; mitochondrial dysfunction; mitochondrial membrane; novel; programs

Project Summary Mitochondria are double-membrane bound organelles that perform many crucial cellular functions, including nucleotide and amino acid metabolism, cellular phospholipid and ion homeostasis, and their most notorious function, generation of cellular energy via oxidative phosphorylation. Mitochondrial form and function are tightly linked. The ability of the organelle to efficiently perform respiration depends on the correct spatial organization of the mitochondrial inner membrane into elaborately shaped morphological domains, including cristae, the hallmark of the organelle. Cristae morphology defects lead to reduced cellular respiration and is a phenotypic consequence of a number of diseases, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s Disease. Despite their importance, we have minimal mechanistic understanding of how cristae are formed and organized within the organelle. Recently, the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex was identified as a master regulator of spatial organization of mitochondria. I previously determined that MICOS is organized into two non-redundant subcomplexes that independently assemble and localize to cristae junctions, a key structural element of the mitochondrial inner membrane. Despite our progress, we have minimal mechanistic understanding of how MICOS contributes to the number, position, and morphogenesis of cristae membranes. In the next five years, our goal is to address these deficits by exploring the molecular basis of MICOS function in yeast cells and, using candidate and forward genetic strategies, determine how MICOS is regulated to fine tune cristae architecture in human cells. This work will lead to insight into the spatial organization of mitochondria and the form-function relationship of the organelle, provide the basis for the future development of my research program, and give us molecular insight into the disorganization of mitochondrial membranes that occurs as a consequence of a number of human diseases.

项目总结