Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons

Hum Mol Genet. 2009 Mar 15;18(6):1028-36. doi: 10.1093/hmg/ddn437. Epub 2008 Dec 18.

Abstract

Age-dependent accumulation of partially deleted mitochondrial DNA (DeltamtDNA) has been suggested to contribute to aging and the development of age-associated diseases including Parkinson's disease. However, the molecular mechanisms underlying the generation and accumulation of DeltamtDNA have not been addressed in vivo. In this study, we have developed a mouse model expressing an inducible mitochondria-targeted restriction endonuclease (PstI). Using this system, we could trigger mtDNA double-strand breaks (DSBs) in adult neurons. We found that this transient event leads to the generation of a family of DeltamtDNA with features that closely resemble naturally-occurring mtDNA deletions. The formation of these deleted species is likely to be mediated by yet uncharacterized DNA repairing machineries that participate in homologous recombination and non-homologous end-joining. Furthermore, we obtained in vivo evidence that DeltamtDNAs with larger deletions accumulate faster than those with smaller deletions, implying a replicative advantage of smaller mtDNAs. These findings identify DSB, DNA repair systems and replicative advantage as likely mechanisms underlying the generation and age-associated accumulation of DeltamtDNA in mammalian neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / metabolism*
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • DNA Breaks, Double-Stranded / drug effects
  • DNA, Mitochondrial / metabolism*
  • Deoxyribonucleases, Type II Site-Specific / metabolism
  • Doxycycline / pharmacology
  • Gene Expression Regulation / drug effects
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism*
  • Organ Specificity / drug effects
  • Sequence Deletion* / drug effects
  • Tetracycline / pharmacology

Substances

  • DNA, Mitochondrial
  • CTGCAG-specific type II deoxyribonucleases
  • Deoxyribonucleases, Type II Site-Specific
  • Tetracycline
  • Doxycycline