Regulation of mitochondrial respiratory complex I

描述（由申请人提供）：哺乳动物NADH脱氢酶（复合体I）受核和线粒体双重遗传控制，在氧化磷酸化中起核心作用。这种呼吸复合体由45个亚基组成，与人类遗传和获得性疾病有关。在之前的研究中，我们已经分离出几种缺乏复合物I组装和线粒体功能的细胞系。我们进一步确定了一个假定的蛋白因子，其过表达与复合体I组装的恢复有关。该提案的具体目标是：1)确定我们鉴定的蛋白质是否为复合体I组装因子2)开发一种分离基因的遗传方法，可以补偿复合体I基因突变引起的线粒体缺陷。该研究的成功将有助于我们了解呼吸复合体I的组装和功能调控，并为开发复合体I缺乏症的治疗方法提供有用的线索。

DESCRIPTION (provided by applicant): The mammalian NADH dehydrogenase (complex I), which is under dual genetic control, nuclear and mitochondrial, plays a central role in oxidative phosphorylation. This respiratory complex consists of 45 subunits and has been implicated in human genetic and acquired diseases. In previous studies, we have isolated several cell lines deficient in complex I assembly and mitochondrial function. We further identified a putative protein factor whose over-expression was associated with recovered complex I assembly. The specific aims of the proposal are to 1) determine if the protein we identified is a complex I assembly factor 2) to develop a genetic approach to isolated genes that could compensate mitochondrial deficiency caused by complex I gene mutations. The success of this proposal will help us to understand the regulation of assembly and function of respiratory complex I, and also provide useful clues for developing a therapeutic approach for complex I deficiency. PUBLIC HEALTH RELEVANCE: We submit this grant application focusing on understanding the function and regulation of mitochondrial respiratory complex I. In particular, we will develop a novel approach to isolate important protein factors which regulate mitochondrial function. The success of this project will advance our understanding of mitochondrial function and shed light on the pathogenesis of human disease associated with complex I dysfunction.