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

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.

Pubmed ID: 19095717

Authors

  • Fukui H
  • Moraes CT

Journal

Human molecular genetics

Publication Data

March 15, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA085700
  • Agency: NCI NIH HHS, Id: R01 CA085700-07
  • Agency: NCI NIH HHS, Id: R01 CA085700-08
  • Agency: NEI NIH HHS, Id: R01 EY010804
  • Agency: NEI NIH HHS, Id: R01 EY010804-13
  • Agency: NEI NIH HHS, Id: R01 EY010804-14A1
  • Agency: NINDS NIH HHS, Id: R01 NS041777
  • Agency: NINDS NIH HHS, Id: R01 NS041777-07
  • Agency: NINDS NIH HHS, Id: R01 NS041777-08
  • Agency: NCI NIH HHS, Id: R01-CA85700
  • Agency: NEI NIH HHS, Id: R01-EY10804
  • Agency: NINDS NIH HHS, Id: R01-NS41777

Mesh Terms

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