Mitochondrial genome mutation in cell death and aging.
This article reviews the concept, molecular genetics, and pathology of cell death and aging in relation to mitochondrial genome mutation. Accumulating evidence emphasizes the role of genetic factors in the development of naturally occurring cell death and aging. The ATP required for a cell's biological activity is almost exclusively produced by mitochondria. Each mitochondrion possesses its own DNA (mtDNA) that codes essential subunits of the mitochondrial energy-transducing system. Recent studies confirm that mtDNA is unexpectedly fragile to hydroxyl radical damage, hence to the oxygen stress. Cellular mtDNA easily fragments into over a hundred-types of deleted mtDNA during the life of an individual. Cumulative accumulation of these oxygen damages and deletions in mtDNA results in a defective energy transducing system and in bioenergetic crisis. The crisis leads cells to the collapse of mitochondrial trans-membrane potential, to the release of the apoptotic protease activating factors into cytosol, to uncontrolled cell death, to tissue degeneration and atrophy, and to aging. The total base sequencing of mtDNA among individuals revealed that germ-line point mutations transmitted from ancestors accelerate the somatic oxygen damages and mutations in mtDNA leading to phenotypic expression of premature aging and degenerative diseases. A practical survey of point mutations will be useful for genetic diagnosis in predicting the life-span of an individual.
Ozawa
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Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan. ozawa@med.nagoya-u.ac.jp
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000502:physiology; D009154:Mutation