Study of redox regulated pathways in the mitochondrion

线粒体氧化还原调节途径的研究

基本信息

批准号：
7615235
负责人：
Deepa Vinay Dabir
金额：
$ 5.01万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/7615235
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

项目摘要

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）：线粒体在能量生产，预防氧化损伤和细胞死亡调节中起关键作用。因此，线粒体功能障碍有助于多种肌肉和神经疾病，包括帕金森氏症，聋哑疾病综合征和雷综合征。此外，在Mohr-Tranebjaerg综合征/聋哑综合征（MTS）患者中，线粒体蛋白进口缺陷与遗传性疾病之间的第一个联系是在遗传性的。这是由一种小的TIM蛋白质中的突变（DDP1，酿酒酵母中的Tim8）引起的。 DDP1组装的主要参与者是蛋白质ERV1，硫酰氧化酶和MIA40。因此，DDP1组装的描述与理解聋哑综合征的分子基础有关。我提出的研究集中在对氧化还原受调节的线粒体膜间空间（IMS）中的进口途径的核心，并且需要DDP1.1的组装来识别ERV1相互作用的蛋白质，以识别包括底物和伴侣蛋白在内的ERV1相互作用的蛋白质，以及（2）重新构建了与Ervide Ervide Ervide protects toctions toction toction tocters protect antv1，MIA40和MIA40和MIA40和MIA40和MIA40和MIA40和MIA40和MIA40和MIA40和MIA40和MIA40和MIA40。 IMS中的这一途径仅在过去三年中被鉴定出来，因此，对该进口途径及其组成部分的完整了解将有助于开发潜在的治疗方法和聋哑疾病综合征和其他破坏性的线粒体疾病的疗法。此外，应该更好地表征进口途径，因为它们可能是治疗化合物的输送系统。最后，我在模型酵母中提出的研究（适合生物化学和遗传学）将为哺乳动物系统中的未来研究提供基础，因为进口在酵母和哺乳动物之间基本上是保守的。该项目对公共卫生很重要，因为有缺陷的线粒体有助于多种神经退行性疾病和肌肉疾病以及衰老。