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Reductive Stress in Complex I Deficiency

复合体 I 缺乏症的还原应激

基本信息

批准号：
8489884
负责人：
MEL B FEANY
金额：
$ 26.46万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8489884
关键词：
Address Adenosine Triphosphate Adult Affect Alexander Disease Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Animals Basal Ganglia Behavioral Binding Biochemical Biochemistry Bioenergetics Biological Biological Assay Biological Models Brain Brain Diseases Brain Stem Cells Cessation of life Child Childhood Clinical Complex Couples Defect Development Disease Disease model Dissection Drosophila genus Electron Transport Electrons Energy Metabolism Evaluation Functional disorder Genetic Genetic Models Genetic Techniques Genome Glutathione Disulfide Human Inborn Errors of Metabolism Inherited Inner mitochondrial membrane Iron Lead Leigh Disease Life Link Lipid Bilayers Live Birth Longevity Measures Mediating Metabolic Diseases Metabolism Mitochondria Mitochondrial Matrix Modeling Multiprotein Complexes Myocardium NADH NADP Necrosis Neuronal Ceroid-Lipofuscinosis Neurons Nuclear Oxidants Oxidative Phosphorylation Parkinson Disease Pathogenesis Pathway interactions Patients Peripheral Production Proton-Motive Force Protons RNA Interference Reactive Oxygen Species Role Series Skeletal Muscle Staging Stress Structure Sulfur Syndrome System Testing Toxic effect Transgenic Organisms Ubiquinone abstracting age related arm disability driving force effective therapy genetic analysis genetic manipulation human disease in vivo Model mitochondrial dysfunction mouse model nervous system disorder neuropathology novel novel therapeutic intervention oligomycin sensitivity-conferring protein public health relevance therapy development

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are central regulators of cellular bioenergetics. Reflecting the critical role for mitochondria in metabolism, energy production, and production of reactive oxygen species, a wide range of human diseases have been linked to mitochondrial dysfunction. Included in these, genetic oxidative phosphorylation disorders represent the most common group of inborn errors of metabolism. Isolated complex I deficiency is the most frequent inherited oxidative phosphorylation disorder and leads to a variety of severe metabolic diseases. Patients with complex I deficiency have a range of clinical presentations that reflect particularly involvement of the brain, heart and skeletal muscle. Leigh's disease, a fatal encephalomyopathy, is the most common clinical syndrome. Isolated complex I deficiency usually leads to death within the first two years of life and there is no effective treatment. Although a substantial amount is know regarding the structure and biochemical function of complex I, the mechanisms leading to cellular dysfunction and death in diseases associated with complex I deficiency are much less well understood. A paucity of animal models has contributed to the slow progress in understanding the pathogenesis of complex I deficiency. To address these issues and allow for a detailed genetic analysis of complex I deficiency, we have modeled the disorder in the simple genetic model organism Drosophila. Results of preliminary genetic modifier analyses lead us to propose a novel hypothesis to explain complex I pathogenesis: accumulation of excess reducing equivalents leading to reductive stress. We will now test the role of reductive stress in complex I deficiency using a combination of genetics and biochemistry. We will first perform a genetic dissection of the enzymatic pathways leading to the production and metabolism of NADH, a critical substrate of complex I. We will then use biochemical assays to measure directly the levels of reductive equivalents in animals with altered complex I function, and in our complex I model in the context of genetically modified backgrounds. If successful, our studies will validate a novel hypothesis regarding the pathogenesis of complex I deficiency and thus set the stage for development of new therapeutic approaches.

描述（由申请人提供）：线粒体是细胞生物能量学的中心调节器。反映了线粒体在代谢、能量产生和活性氧物质产生中的关键作用，广泛的人类疾病与线粒体功能障碍有关。其中，遗传性氧化磷酸化障碍是最常见的先天性代谢缺陷。孤立性复合物I缺乏症是最常见的遗传性氧化磷酸化障碍，并导致多种严重的代谢性疾病。复合物I缺乏的患者有一系列的临床表现，特别反映了大脑，心脏和骨骼肌的参与。利氏病是一种致命的脑肌病，是最常见的临床综合征。孤立的复合物I缺乏症通常会导致生命的头两年内死亡，并且没有有效的治疗方法。虽然关于复合物I的结构和生物化学功能已经知道了相当多的信息，但导致与复合物I缺乏相关的疾病中的细胞功能障碍和死亡的机制还不太清楚。动物模型的缺乏导致了对复合物I缺乏症发病机制的理解进展缓慢。为了解决这些问题，并允许复杂的I缺陷的详细遗传分析，我们模拟了简单的遗传模式生物果蝇的疾病。初步遗传修饰分析的结果使我们提出了一个新的假说来解释复杂的I发病机制：积累过量的还原当量导致还原应力。我们现在将结合遗传学和生物化学来测试还原应激在复合物I缺乏中的作用。我们将首先对导致复合物I的关键底物NADH的产生和代谢的酶途径进行遗传解剖。然后，我们将使用生物化学测定来直接测量具有改变的复合物I功能的动物中的还原当量的水平，以及在我们的复合物I模型中的转基因背景的情况下。如果成功，我们的研究将验证有关复合物I缺乏症发病机制的新假设，从而为开发新的治疗方法奠定基础。