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

Hirokazu Fukui, Carlos T. Moraes

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

Age-dependent accumulation of partially deleted mitochondrial DNA (ΔmtDNA) 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 ΔmtDNA 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 ΔmtDNA 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 ΔmtDNAs 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 ΔmtDNA in mammalian neurons.

Original languageEnglish (US)
Pages (from-to)1028-1036
Number of pages9
JournalHuman molecular genetics
Volume18
Issue number6
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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