Mitochondrial microheteroplasmy and a theory of aging and age-related disease.
We implicate a recently described form of mitochondrial mutation, mitochondrial microheteroplasmy, as a candidate for the principal component of aging. Microheteroplasmy is the presence of hundreds of independent mutations in one organism, with each mutation usually found in 1-2% of all mitochondrial genomes. Despite the low abundance of single mutations, the vast majority of mitochondrial genomes in all adults are mutated. This mutational burden includes inherited mutations, de novo germline mutations, as well as somatic mutations acquired either during early embryonic development or later in adult life. We postulate that microheteroplasmy is sufficient to explain the pathomechanism of several age-associated diseases, especially in conditions with known mitochondrial involvement, such as diabetes (DM), cardiovascular disease, Parkinson's disease (PD), and Alzheimer's disease (AD) and cancer. The genetic properties of microheteroplasmy reconcile the results of disease models (cybrids, hypermutable PolG variants and mitochondrial toxins), with the relatively low levels of maternal inheritance in the aforementioned diseases, and provide an explanation of their delayed, progressive course.
Smigrodzki
Rafal M
RM
Gencia Corporation, Charlottesville, Virginia 22903, USA. rafal@genciabiotech.com
Khan
Shaharyar M
SM
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D004194:Disease; D016678:Genome; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000502:physiology*
D004272:DNA, Mitochondrial