Gene expression and its abnormality in mitochondrial electron-transfer enzyme deficiency.

线粒体能量传递系统在遗传上受核DNA和线粒体DNA的双重控制。为了阐明电子转移酶缺乏症的基因表达及其异常，我们采用酶亚基免疫化学分析和线粒体DNA分子生物学分析等方法，获得了以下结果.电子传递复合物缺陷的分子组装异常：我们在一名肌病患者中发现了复合物IV（细胞色素c__-氧化酶）的神经编码亚基2的缺陷。我们阐明了MELAS（线粒体肌病、脑病、乳酸酸中毒和卒中样发作）的病因是复合物I（NADH-泛醌氧化还原酶）亚基和铁硫簇的不成比例的缺乏。从这些结果我们推测，电子转移复合物的分子组装受到干扰可能是由于电子编码亚基的缺陷.肥厚型心肌病的病因：我们检测了4例心肌病和MELAS患者的骨骼肌线粒体，发现复合物I亚单位的缺陷是一种肥厚型心肌病的病因.线粒体DNA缺失的母系遗传：在一个患有慢性进行性眼外肌麻痹的家族中，我们发现母亲和女儿都有线粒体DNA缺失。这是第一次证明线粒体DNA突变导致人类母系传播疾病，因此，我们的研究揭示了线粒体DNA突变是人类多种疾病的病因。目前正在使用新开发的聚合酶链反应方法对线粒体DNA突变进行进一步分析。

The mitochondrial energy-transducing system is genetically under the dual control by nuclear and mitochondrial DNA. To elucidate the gene expression and its abnormality in electron-transfer enzyme deficiency, we made multiple approaches, such as immunochemical analysis of enzyme subunits and molecular biologic analysis of mitochondrial DNA, and obtained the following rasults.1. Abnormality of molecular assembly in electron-transfer complex deficiency:We found a defect of mitochondrially encoded subunit 2 of Complex IV (cytochrome c__- oxidase) in a patient with myopathy. We elucidated that the etiology of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) is the disproportionate deficiency of subunits and iron-sulfur clusters of Complex I (NADH-ubiquinone oxidoreductase). We speculated from these results that the molecular assembly of electron-transfer complexes is disturbed probably due to the defects of mitochondrially encoded subunits.2. The etiology of hypertrophic cardiomyopathy: We examined the skeletal muscle mitochondria from four patients with cardiomyopathy and MELAS, and found that the defects of Complex I subunits is the etiology of a type of hypertrophic cardiomyopathy.3. Maternal inheritance of deleted mitochondrial DNA: In a family with chronic progressive external ophthalmoplegia, we showed that a mother and a daughter had mitochondrial DNA deletions. This was the first demonstration that mitochondrial DNA mutation causes a maternally transmitted human disease.Thus, our study has revealed that mitochondrial DNA mutation is the etiology of various human diseases. Further analysis of mitochondrial DNA mutations is now underway using the newly developed polymerase chain reaction method.