Spatial Organization of the Mitochondrial Inner Membrane

项目摘要 线粒体是双膜结合的细胞器，执行许多重要的细胞功能，包括 核苷酸和氨基酸代谢，细胞磷脂和离子稳态，以及它们最臭名昭著的 功能，通过氧化磷酸化产生细胞能量。线粒体的形态和功能 有联系细胞器有效进行呼吸的能力取决于正确的空间组织 线粒体内膜的细胞分裂成精心塑造的形态结构域，包括嵴， 细胞器的标志嵴形态缺陷导致细胞呼吸减少，是一种表型 许多疾病的后果，包括神经退行性疾病，如阿尔茨海默氏症和 帕金森氏症尽管它们很重要，但我们对嵴是如何形成的机械理解很少。 在细胞器内形成和组织。最近，线粒体接触位点和嵴组织 系统（MICOS）复合物被确定为线粒体空间组织的主要调节因子。我 先前确定MICOS被组织成两个非冗余子复合体， 组装并定位于嵴连接处，这是线粒体内膜的关键结构元件。 尽管我们取得了进展，但我们对MICOS如何对数字做出贡献的机械理解很少， 嵴膜的位置和形态发生。在未来五年，我们的目标是解决这些赤字 通过探索酵母细胞中MICOS功能的分子基础，并使用候选和正向遗传学方法， 战略，确定如何MICOS是调节微调嵴结构在人类细胞。这项工作将 导致深入了解线粒体的空间组织和细胞器的形式-功能关系， 为我的研究计划的未来发展提供了基础，并让我们从分子上深入了解 由于许多人类疾病而发生的线粒体膜的紊乱。

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.