The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations.

Abstract

Mitochondria are cellular energy factories that generate ATP via the reaction of hydrocarbons with oxygen. Every human cell contains hundreds of mitochondria, and each mitochondrion contains multiple copies of mitochondrial DNA (mtDNA). The ancestry of the mitochondrial genome can be traced to early eubacteria, and it is therefore unexpected that this organelle may have a major role in governing the pace of human aging. Three recent papers (1–3) plus a work published in a recent issue of PNAS (4) have demonstrated that accelerating the mtDNA mutation rate can result in some features suggestive of premature aging, consistent with the view that loss of mitochondrial function is a major causal factor in aging. mtDNA polymerase (Pol-γ) is the only DNA polymerase that is known to be targeted to and that resides in mitochondria (5). In the absence of other known mtDNA polymerases, it is assumed that Pol-γ is responsible for all aspects of mtDNA synthesis, including replication of the mitochondrial genome and repair of DNA damage. As is the case for many other DNA polymerases, the high fidelity of Pol-γ derives from both selection for the correct incoming nucleotide and excision of misincorporated nucleotides by a 3′ → 5′ exonucleolytic proofreading activity (6). Elimination of proofreading by replacement of critical aspartic acid residues in the exonuclease domain with alanine increases misincorporation; in vitro , this misincorporation is manifested predominantly as single base substitutions (7). Both the Larsson (1) and Prolla (2) groups replaced in embryonic stem cells POLG, the …