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

Hirokazu Fukui, Carlos T Moraes

Research output: Contribution to journalArticle

122 Citations (Scopus)

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
Pages (from-to)1028-1036
Number of pages9
JournalHuman Molecular Genetics
Volume18
Issue number6
DOIs
StatePublished - Mar 13 2009

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Mitochondrial DNA
Neurons
Homologous Recombination
DNA Repair
Parkinson Disease
Mitochondria
DNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. / Fukui, Hirokazu; Moraes, Carlos T.

In: Human Molecular Genetics, Vol. 18, No. 6, 13.03.2009, p. 1028-1036.

Research output: Contribution to journalArticle

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