Study of redox regulated pathways in the mitochondrion

线粒体氧化还原调节途径的研究

• 批准号: 7916668
• 负责人: Deepa Vinay Dabir
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916668
• 关键词: ATP Synthesis Pathway; Aging; Animal Model; Apoptosis; Bacteria; Biochemical; Biochemical Genetics; Biochemistry; Biogenesis; Cell Death; Cells; Chemistry; Complex; Cytochrome c Peroxidase; Defect; Development; Disease; Disulfides; Dystonia; Electron Transport; Electrons; Environment; Eukaryotic Cell; Figs - dietary; Future; Genetic; Goals; Homeostasis; Homologous Gene; In Vitro; Inherited; Ions; Knowledge; Laboratories; Leigh Disease; Link; Mammals; Mediating; Membrane; Metabolism; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Mohr-Tranebjaerg syndrome; Molecular; Muscle; Mutation; Myopathy; Nerve Degeneration; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen; Parkinson Disease; Pathway interactions; Patients; Plants; Play; Population; Prevention; Production; Property; Protein Import; Proteins; Proteome; Public Health; Publishing; Reaction; Reactive Oxygen Species; Recycling; Regulation; Research; Respiration; Respiratory Chain; Ring Finger Domain; Role; Saccharomyces cerevisiae; Syndrome; System; Therapeutic; Work; Yeast Model System; Yeasts; Zinc; base; cysteine rich protein; cytochrome c; deafness; disulfide bond; dystonia-deafness syndrome; insight; mitochondrial dysfunction; novel; oxidation; oxidative damage; periplasm; protein folding; reconstitution; relating to nervous system; sulfhydryl oxidase; translocase

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.

描述（由申请人提供）：线粒体在能量产生、预防氧化损伤和调节细胞死亡中发挥着关键作用。因此，线粒体功能障碍会导致多种肌肉和神经疾病，包括帕金森病、耳聋肌张力障碍综合征和利氏综合征。此外，线粒体蛋白输入缺陷与遗传性疾病之间的首次联系是在 Mohr-Tranebjaerg 综合征/耳聋肌张力障碍综合征 (MTS) 患者中发现的。这是由一种小 Tim 蛋白（酿酒酵母中的 DDP1、Tim8）突变引起的。 DDP1 组装的关键参与者是蛋白质 Erv1（一种巯基氧化酶）和 Mia40。因此，DDP1 组装的描述有助于理解耳聋肌张力障碍综合征的分子基础。我提出的研究中心是表征进入线粒体膜间空间 (IMS) 的输入途径，该途径受氧化还原调节，并且是 DDP1.1 组装所需的。建议 (1) 识别 Erv1 相互作用蛋白，包括底物和伴侣蛋白，以及 (2) 重建与 Erv1、Mia40 和潜在伴侣蛋白的二硫键交换反应。 IMS 中的这条通路是在过去三年才被确定的，因此，对该输入通路及其组成部分的完整了解将有助于开发针对耳聋肌张力障碍综合征和其他破坏性线粒体疾病的潜在治疗方法和治疗方法。此外，应该更好地表征输入途径，因为它们可能充当治疗化合物的递送系统。最后，我提出的模型酵母研究，适用于生物化学和遗传学，将为未来在哺乳动物系统中的研究提供基础，因为酵母和哺乳动物之间的输入在很大程度上是保守的。该项目对公共健康非常重要，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。