| First Author | Fukui H | Year | 2009 |
| Journal | Hum Mol Genet | Volume | 18 |
| Issue | 6 | Pages | 1028-36 |
| PubMed ID | 19095717 | Mgi Jnum | J:145737 |
| Mgi Id | MGI:3835906 | Doi | 10.1093/hmg/ddn437 |
| Citation | Fukui H, et al. (2009) Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum Mol Genet 18(6):1028-36 |
| abstractText | 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. |
