Study of redox regulated pathways in the mitochondrion

描述（由申请人提供）：该蛋白在能量产生、预防氧化损伤和调节细胞死亡中起关键作用。因此，线粒体功能障碍导致广泛的肌肉和神经疾病，包括帕金森氏症、肥胖-肌张力障碍综合征和利氏综合征。此外，线粒体蛋白质输入缺陷与遗传性疾病之间的第一个联系是在Mohr-Tranebjaerg综合征/肌张力障碍综合征（MTS）患者中发现的;这是由一种小Tim蛋白（S. cerevisiae）。DDP 1组装的关键参与者是蛋白质Erv 1（一种巯基氧化酶）和Mia 40。因此，DDP 1装配的描绘与理解肥胖-肌张力障碍综合征的分子基础有关。我建议的研究中心的特征的输入途径到线粒体膜间隙（IMS），是氧化还原调节，并需要装配的DDP 1.1建议（1）确定Erv 1相互作用的蛋白质，包括底物和伴侣蛋白，（2）重建二硫键交换反应与Erv 1，Mia 40和潜在的伴侣蛋白。IMS中的这一途径仅在过去三年中被确定，因此，对这一输入途径及其组分的完整了解将有助于开发针对肥胖-肌张力障碍综合征和其他破坏性线粒体疾病的潜在治疗和疗法。此外，应更好地表征输入途径，因为它们可能作为治疗化合物的递送系统。最后，我提出的研究模式酵母，这是服从生物化学和遗传学，将提供基础，为今后的研究在哺乳动物系统中，因为进口在很大程度上是保守的酵母和哺乳动物之间。这个项目对公共卫生很重要，因为有缺陷的线粒体会导致广泛的神经退行性疾病和肌肉疾病以及衰老。

DESCRIPTION (provided by applicant): The mitochondrion plays a key role in energy production, prevention of oxidative damage and regulation of cell death. Consequently, mitochondrial dysfunction contributes to a broad range of muscular and neural disorders, including Parkinson's, deafness-dystonia syndrome, and Leigh's syndrome. Furthermore, the first connection between a defect in mitochondrial protein import and an inherited disease was made in patients with Mohr-Tranebjaerg syndrome/deafness-dystonia syndrome (MTS); this is caused by mutations in one of the small Tim proteins (DDP1, Tim8 in S. cerevisiae). Key players in assembly of DDP1 are proteins Erv1, a sulfhydryl oxidase, and Mia40. Thus, delineation of DDP1 assembly is pertinent to understanding the molecular basis of deafness-dystonia syndrome. My proposed research centers on characterization of an import pathway into the mitochondrial intermembrane space (IMS) that is redox regulated and is required for the assembly of DDP1.1 propose (1) to identify Erv1 interacting proteins including substrates and partner proteins, and (2) to reconstitute the disulfide exchange reaction with Erv1, Mia40 and potential partner proteins. This pathway in the IMS has only been identified in the past three years and thus, a complete knowledge of this import pathway and its components would aid in development of potential treatments and therapies for deafness-dystonia syndrome and other devastating mitochondrial diseases. Additionally, import pathways should be better characterized because they might serve as delivery systems for therapeutic compounds. Lastly, my proposed studies in the model yeast, which is amenable to biochemistry and genetics, will provide the basis for future studies in mammalian systems because import is largely conserved between yeast and mammals. This project is important to public health because defective mitochondria contribute to a broad range of neurodegenerative and muscular diseases as well as aging.