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Human Molecular Genetics Advance Access originally published online on December 18, 2008
Human Molecular Genetics 2009 18(6):1028-1036; doi:10.1093/hmg/ddn437
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Hirokazu Fukui1,{dagger} and Carlos T. Moraes1,2,3,*

1 Neuroscience Program 2 Department of Neurology 3 Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33136, USA

* To whom correspondence should be addressed at: Department of Neurology, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Tel: +1 3052435858; Fax: +1 3052433914; Email: cmoraes{at}med.miami.edu

Received November 20, 2008; Accepted December 16, 2008

Age-dependent accumulation of partially deleted mitochondrial DNA ({Delta}mtDNA) 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 {Delta}mtDNA 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 {Delta}mtDNA 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 {Delta}mtDNAs 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 {Delta}mtDNA in mammalian neurons.

{dagger} Present address: Department of Genetics, Stanford University, Stanford, CA 94305, USA.


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