Diversity Supplement for 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紧密相连 已链接。细胞器进行有效呼吸的能力取决于正确的空间组织。 线粒体内膜形成精致的形态结构域，包括脊， 细胞器的标志。冠状突起形态缺陷导致细胞呼吸减少，是一种表型 一些疾病的后果，包括阿尔茨海默氏症和老年痴呆症等神经退行性疾病 帕金森氏症。尽管它们很重要，但我们对海脊是如何的机械了解很少。 在细胞器内形成和组织的。近年来，线粒体接触部位和海脊组织化 MICOS系统复合体被认为是线粒体空间组织的主要调节因子。我 先前确定MICOS被组织成两个独立的非冗余子复合体 组装并定位到冠状连接，这是线粒体内膜的关键结构元素。 尽管我们取得了进展，但我们对MICOS如何影响这一数字的机械理解很少， 冠膜的位置和形态发生。我们将通过探索分子机制来解决这些缺陷 酵母细胞中MICOS功能的基础，并使用候选和正向遗传策略，确定如何 MICOS受到调控，以微调人类细胞的脊状突结构。这项工作将导致对空间的洞察 线粒体的组织和细胞器的形态-功能关系，为未来的研究提供了基础 我的研究项目的发展，并让我们从分子上了解线粒体的解体 由于多种人类疾病而产生的细胞膜。

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. We will 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.