Different faces of mitochondrial DNA mutators

Biochim Biophys Acta. 2015 Nov;1847(11):1362-72. doi: 10.1016/j.bbabio.2015.05.016. Epub 2015 May 23.

Abstract

A number of studies have shown that ageing is associated with increased amounts of mtDNA deletions and/or point mutations in a variety of species as diverse as Caenorhabditis elegans, Drosophila melanogaster, mice, rats, dogs, primates and humans. This detected vulnerability of mtDNA has led to the suggestion that the accumulation of somatic mtDNA mutations might arise from increased oxidative damage and could play an important role in the ageing process by producing cells with a decreased oxidative capacity. However, the vast majority of DNA polymorphisms and disease-causing base-substitution mutations and age-associated mutations that have been detected in human mtDNA are transition mutations. They are likely arising from the slight infidelity of the mitochondrial DNA polymerase. Indeed, transition mutations are also the predominant type of mutation found in mtDNA mutator mice, a model for premature ageing caused by increased mutation load due to the error prone mitochondrial DNA synthesis. These particular misincorporation events could also be exacerbated by dNTP pool imbalances. The role of different repair, replication and maintenance mechanisms that contribute to mtDNA integrity and mutagenesis will be discussed in details in this article. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.

Keywords: Ageing; Mitochondrial DNA repair; POLG; mtDNA mutations; mtDNA replication.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging*
  • Animals
  • DNA Helicases / physiology
  • DNA Polymerase gamma
  • DNA Repair
  • DNA Replication
  • DNA, Mitochondrial / genetics*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / physiology
  • Humans
  • Mitochondrial Proteins / physiology
  • Mutation*

Substances

  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human
  • DNA Helicases
  • TWNK protein, human