Cell-by-Cell analysis of mtDNA Mutations and the Mitochondrial Theory of Aging





Y. Kraytsberg, E. Nekhaeva, N. B. Bodyak and K. Khrapko

Division on Aging, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA



A number of attractive hypotheses postulate that age-dependent accumulation of somatic mtDNA mutations is responsible for certain aspects of the aging process. Since every cell contains hundreds of mitochondrial genomes, a somatic mutation needs to amass in a cell before it can affect cellular physiology. The studies of age-dependent accumulation of mtDNA mutations at the whole tissue level should therefore be complemented by studies of their intracellular distribution. Single-cell analysis of mtDNA mutations have demonstrated that somatic mutations in mtDNA are prone to intracellular clonal expansions, ultimately leading to completely mutant cells. The absolute frequency of cells with expanded somatic mutations is rather high, and most likely every cell in an aged human tissue contains at least one expanded mutation. We also took advantage of heteroplasmic human tissues (i.e. those containing a mixture of two mtDNA genotypes). As expected, the two genotypes tend to be proportionally represented in the cells of the young tissue. In contrast, in the old tissue, the two genotypes tend to be segregated into separate cells. This is exactly what one would expect if intracellular expansions of mtDNA genomes were common. These findings confirm that expansion of mitochondrial genomes is a common process, which proceeds in parallel to age-dependent accumulation of somatic mtDNA mutations. It is not clear whether expansions are driven by specific somatic mutations or this process is independent of mutations. In any case, from the mitochondrial mutation point of view, the aged tissue appears to be characterized not only by a higher incidence of mutations, but also by an increased proportion of cells where these mutations have attained complete or partial homoplasmy. The two tendencies may work cooperatively to enhance the physiological impact of somatic mitochondrial mutations and augment their role in the aging process.

Reference: E. Nekhaeva, et al. "Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues." Proc. Natl. Acad. Sci. 2002, 99:5521-5526




Key words: aging, mitochondria, mutation, clonal expansion







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