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

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

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  • 1Neuroscience Program, University of Miami School of Medicine, Miami, FL 33136, USA.

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.

PMID:
19095717
PMCID:
PMC2722231
DOI:
10.1093/hmg/ddn437
[PubMed - indexed for MEDLINE]
Free PMC Article
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