High frequency of somatic mutations in rat liver mitochondrial DNA.

Somatic mutations in mitochondrial DNA (mtDNA) are thought to play an important role in both aging and neurodegenerative diseases although their specific contributions remain a subject of intense debate. We analyzed somatic mutations in the mtDNA control regions in the liver of Wistar rats. The mutation rate was found to be high and increased with age from 5.3x10(-4) mutations per position to 4.48x10(-3) mutations per position at 3 and 12 months of age, respectively. The vast majority of nucleotide substitutions are transitions ( approximately 95%) with A:T>G:C transitions being the most frequent type of substitution (>50%). In 3-month-old Wistar rats, approximately 40% of somatic mutations in the control region of mtDNA are significantly consistent with the model of dislocation mutagenesis which is a signature of error-prone DNA synthesis by mtDNA polymerase gamma. The results are consistent with the previous hypothesis that normal intramitochondrial dNTP pool asymmetries, which have been shown to reduce the fidelity of mtDNA polymerase gamma, substantially contribute to somatic mutagenesis of the rat mtDNA.