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的中央调节器。许多人类疾病都与线粒体功能障碍有关，这反映了线粒体在新陈代谢、能量产生和活性氧产生中的关键作用。其中，遗传性氧化磷酸化障碍代表了最常见的先天性代谢错误。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，可导致多种严重的代谢疾病。复合物 I 缺乏症患者有一系列临床表现，尤其反映了大脑、心脏和骨骼肌的受累。利氏病是一种致命性脑肌病，是最常见的临床综合征。孤立的复合物 I 缺乏通常会导致出生后两年内死亡，并且没有有效的治疗方法。尽管人们对复合物 I 的结构和生化功能了解很多，但对于复合物 I 缺乏相关疾病中导致细胞功能障碍和死亡的机制却知之甚少。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对复合物 I 缺乏症进行详细的遗传分析，我们在简单的遗传模型生物果蝇中模拟了这种疾病。初步遗传修饰分析的结果使我们提出了一个新的假设来解释复合体 I 的发病机制：过量还原当量的积累导致还原应激。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 缺乏症中的作用。我们将首先对导致 NADH（复合物 I 的关键底物）产生和代谢的酶途径进行基因剖析。然后，我们将使用生化测定直接测量复合物 I 功能改变的动物中还原当量的水平，并在我们的复杂 I 模型中，在转基因背景下。如果成功，我们的研究将验证关于复合物 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。