Mutation and oxidative damage of mitochondrial DNA and defective turnover of mitochondria in human aging.
Accumulation of somatic mutations in the mitochondrial DNA (mtDNA) is a major contributor to human aging and degenerative diseases. Rapid progress has been made in unraveling the molecular changes associated with aging. MtDNA mutations are likely early molecular events associated with human aging that may be responsible for the age-dependent decline in mitochondrial respiratory functions. Many types of mutations of the mitochondrial genome impair the function of the respiratory and oxidative phosphorylation systems. This not only results in the age-dependent decline in cellular functions, but also increases the generation of reactive oxygen species (ROS) through the respiratory chain. ROS may cause oxidative damage to mtDNA, further impairing cellular functions and thereby increasing the rate of aging. How aging is elicited by the relatively low amount (< 5%) of aging-associated mutated mtDNA in human tissues is poorly understood. Protein degradation may be a key mechanism in the formation of lipofuscin and possibly in cellular aging. The thiol proteases, critical for protein turnover and degradation, are particularly susceptible to free radical damage at their active sites. If the degradative pathway in mitochondria is defective, the mitochondrion-derived degradation intermediates accumulate within secondary lysosomes, leading to the formation of residual bodies. These degradation products may become another "stressor" to tissue cells. We therefore propose that defective mitochondrial turnover is a cause of accumulation of defective mitochondrial constituents and an important contributory factor to human aging.
Lee
H C
HC
Department of Biochemistry, National Yang-Ming University, Taipei, Taiwan, ROC.
Wei
Y H
YH
D000375:Aging / Q000378:metabolism*; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism*
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species