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

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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.