Mutation and intracellular clonal expansion of mitochondrial genomes: two synergistic components of the aging process?

The foundations of the Mitochondrial mutational theory of aging include two assumptions: the high abundance of mitochondrial mutations and their ability to clonally expand within individual cells. The up-to-date data pertinent to these assumptions is reviewed and semi-quantitative estimates of the frequencies of mutants and intracellular expansions are offered. The incidence of mutations in various aged tissues may be on the order of one mutant per mitochondrial genome copy, and most of the cells are likely to be affected by intracellular clonal expansions of mitochondrial genomes.

Clonal expansions of mitochondrial genomes: implications for in vivo mutational spectra.

It is often assumed mutant frequencies, as measured in a DNA sample, faithfully represent basic mutation rates associated with these mutations. This paradigm was extremely helpful for in vitro studies of the mechanisms of mutagenesis/repair and causes of mutations. However, in vivo, mutant fractions appear to vary dramatically and randomly from sample to sample.

mtLOH (mitochondrial loss of heteroplasmy), aging, and 'surrogate self'.

In tribute to Dr Strehler, an attempt is made to use a style of reasoning found in some of his later papers as an outline of this article. First, general arguments in favor of the involvement of somatic mutations in mtDNA in the aging process are presented. Second, evidence is provided in support of a general tendency of mitochondrial genomes to reach homoplasmic state at the cellular level, for which we propose the term mitochondrial loss of heteroplasmy (mtLOH).

Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues.

Using single-cell sequence analysis, we discovered that a high proportion of cells in tissues as diverse as buccal epithelium and heart muscle contain high proportions of clonal mutant mtDNA expanded from single initial mutant mtDNA molecules. We demonstrate that intracellular clonal expansion of somatic point mutations is a common event in normal human tissues. This finding implies efficient homogenization of mitochondrial genomes within individual cells.