Article

Fukui, H. & Moraes, C. T. Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum. Mol. Genet. 18, 1028-1036

Neuroscience Program, University of Miami School of Medicine, Miami, FL 33136, USA.
Human Molecular Genetics (Impact Factor: 6.39). 01/2009; 18(6):1028-36. DOI: 10.1093/hmg/ddn437
Source: PubMed

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.

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    • "The integrity of mitochondrial DNA plays a critical role in maintaining cellular homeostasis and efficient repair of mtDNA damage is important for cellular survival. When DSBs are induced in mitochondria by restriction endonucleases, both intramolecular and intermolecular recombination products with large deletions are observed (Fukui and Moraes, 2009). Although homologous recombination could be one of the potential pathways of mtDNA DSB repair to ensure stability of the genome, evidence to this end in mitochondria is lacking. "
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    • "To study the molecular mechanisms underlying the generation and accumulation of mtDNA deletions in neurons in vivo, mice expressing neuron-specific mito-PstI were created by crossing the TRE-mito-PstI mouse with a model carrying the tTA gene under the control of the Cam- KIIa promoter (Fukui & Moraes, 2009). In the absence of Dox, CamKIIαtTA drives the expression of mito-PstI in forebrain neurons. "
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