MOLECULAR REMEDY OF MITOCHONDRIAL DEFECTS

描述：最近几年的研究表明，结构和 线粒体质子转运NADH-泛醌的功能缺陷 氧化还原酶(复合体I)与许多人类疾病有关。这些 疾病包括Leber遗传性视神经病变，帕金森氏症 疾病，肌张力障碍，严重的乳酸酸中毒，各种形式的 脑肌病，可能还有亨廷顿氏病。失调症 复合体I提出了三个问题：(1)能力受损 呼吸链将NADH氧化回所需的NAD4，其中 其他用于柠檬酸循环和脂肪酸运行的东西 氧化酶。(2)该酶的泵送能力受损 质子，导致ATP合成速率下降。(3) 产生超氧阴离子自由基，导致线粒体DNA(MtDNA) 突变、脂质过氧化和蛋白质变性。 哺乳动物复合体I由至少41个不同的亚基组成，具有 膜结合酶复合体中最复杂的结构。 在这些亚基中，有7个由mtdna编码，并在 线粒体等是细胞体的产物。目前， 线粒体DNA编码的亚基的突变和缺失不是 由核ONA编码的多个亚基的可纠正和突变 (NDNA)很难修复。这笔赠款的总体目标是 应用程序是为了找到治疗由以下原因引起的疾病的药物 复合体I的功能障碍。

DESCRIPTION: It has been shown in recent years that structural and functional defects of mitochondrial proton-translocating NADH-ubiquinone oxidoreductase (complex I) are involved in many human diseases. These diseases include Leber's hereditary optic neuropathy, Parkinson's disease, dystonia, severe lactic acidosis, various forms of encephalomyopathies, and possibly Huntington's disease. Dysfunction of complex I presents three problems: (1) Impairment of the ability of the respiratory chain to oxidize NADH back to NAD4 which is required, among other things, for operation of the citric acid cycle and fatty acid oxidation enzymes. (2) Impairment of the ability of this enzyme to pump protons, resulting in a decrease in the rate of ATP synthesis. (3) Production of superoxide radicals, causing mitochondrial DNA (mtDNA) mutation, lipid peroxidation, and protein denaturation. Mammalian complex I is composed of at least 41 unlike subunits and has the most intricate structure among the membrane-bound enzyme complexes. Of these subunits, seven are encoded by mtDNA and synthesized within the mitochondrion, and other are cytoribosomal products. At present, mutations and deletions of the subunits encoded by MtDNA are not correctable, and mutations of plural subunits encoded by nuclear ONA (nDNA) are difficult to repair. The overall goal of this grant application is to find a remedy for the diseases that result from dysfunction of complex I.