Mutations of mitochondrial DNA - cause or consequence of the ageing process?
Ageing is a stochastic process which leads to a gradual decline in cellular, tissue and even organ function, especially in energy dependent postmitotic tissues like skeletal muscle, brain and heart. The mitochondrial theory of ageing is based on the assumption that reactive oxygen species (ROS) and free radicals generated in the immediate vicinity of the electron transport chain during the lifespan of an organism damage proteins, lipids and mitochondrial DNA (mtDNA). Whereas it was generally believed that mitochondria are among the important players regarding the ageing process, two recent important approaches shed new light on the complex interactions. It has been shown by single cell experiments and computer simulation models that mitochondrial mutations are generated stochastically in childhood or early adolescence and accumulate clonally in a cell or muscle fibre, leading to a local age related impairment of cellular energy supply. Other important observations come from mitochondrial mutator mice, harbouring mitochondrial mutations due to a deficient repair enzyme (POLG). These mice reveal a premature senescence but do not exhibit a vicious cycle of increased oxidative damage or ROS production as has been postulated by the mitochondrial theory of ageing. At the moment it is hard to decide, if mitochondrial mutations are the cause or consequence of human ageing, but it is suggested that mitochondrial point mutations are just the consequence, while deletions seem to play a causal role.
Meissner
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Department of Forensic Medicine, University Hospital of Schleswig-Holstein, Kahlhorststrasse 31-35, 23562, Lübeck, Germany. meissner@rmed.mu-luebeck.de
D000375:Aging / Q000235:genetics*; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics
D004272:DNA, Mitochondrial