Mechanism of somatic mitochondrial DNA mutations associated with age and diseases.
Mitochondrial DNA (mtDNA) that codes protein subunits essential for the maintenance of mitochondrial ATP synthesis system acquires mutations at a much higher rate than that in nuclear DNA. Recent study has revealed that somatically acquired mutations such as deletions in mtDNA are caused mainly by oxygen free-radical damage. Cumulative accumulation of these somatic mutations during the life of an individual causes bioenergetic deficit leading to cell death and normal ageing. The base-sequencing of the entire mtDNA from 48 individuals revealed that germ-line point mutations accelerate extensively the somatic oxygen free-radical damage and the deletions leading to generation of more than a hundred kinds of mtDNA minicircle. These accelerated somatic mutations are expressed as premature ageing of the patients with degenerative diseases. Comprehensive analyses of the entire mtDNA, including the total base-sequencing and the total deletion correlating with oxygen free-radical damage, has revealed a clear relationship between the genotype and its phenotype, such as the severity of clinical symptoms and the survival time of the patients. Extensive generation of mtDNA minicircles caused by the oxygen free radical implies a close relations between the redox mechanism of ageing and the programmed cell-death machinery.
Ozawa
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Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan.
D000375:Aging / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D003573:Cytochrome b Group / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008931:Mitochondria, Muscle / Q000473:pathology / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D006180:Proton-Translocating ATPases / Q000235:genetics*
D003573:Cytochrome b Group; D004272:DNA, Mitochondrial; D006180:Proton-Translocating ATPases