Accumulation of defective mitochondria through delayed degradation of damaged organelles and its possible role in the ageing of post-mitotic and dividing cells

The mitochondrial theory of ageing proposes that an accumulation of defecti ve mitochondria is a major contributor to the cellular deterioration that u nderlies the ageing process. The plausibility of the mitochondrial theory d epends critically upon the population dynamics of intact and mutant mitocho ndria in different cell types. Earlier work suggested that mutant mitochond ria might have a replication advantage but failed to account for the fact t hat mutants accumulate faster in post-mitotic than in dividing cells. We de scribe a new mathematical model that allows for damaged mitochondria to rep licate more slowly, which accommodates experimental evidence of impaired en ergy generation and a reduced proton gradient in defective mitochondria. Ho wever, this is compensated for by a slower degradation rate of damaged mito chondria than intact ones, as suggested by de Grey (1997), which gives dama ged mitochondria a selective advantage and leads to a clonal expansion of d amaged mitochondria. This theoretical result is important because it agrees with evidence that, during ageing, single muscle fibres are taken over by one or only a few types of mtDNA mutants. The model also shows that cell di vision can rejuvenate and stabilize the mitochondrial population, consisten t with data that post-mitotic tissues accumulate mitochondrial damage faste r than mitotically active tissues. (C) 2000 Academic Press.