Regulation of mitochondrial respiratory complex I

描述(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，在氧化磷酸化过程中起核心作用。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。在以前的研究中，我们已经分离了几个缺乏复合体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质因子，它的过度表达与恢复的复合体I组装有关。该提案的具体目的是1)确定我们确定的蛋白质是否是复杂的I组装因子2)开发一种分离基因的遗传方法，以弥补复杂的I基因突变导致的线粒体缺陷。这个方案的成功将有助于我们了解呼吸复合体I的组装和功能的调节，也将为开发复杂I缺乏症的治疗方法提供有用的线索。 公共卫生意义：我们提交这项拨款申请，重点是了解线粒体呼吸复合体I的功能和调节，特别是，我们将开发一种新的方法来分离调节线粒体功能的重要蛋白质因子。该项目的成功将促进我们对线粒体功能的了解，并为揭示与复杂I功能障碍相关的人类疾病的发病机制提供线索。

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.