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. 2005 Apr 5;102(14):4990-5.
doi: 10.1073/pnas.0500253102. Epub 2005 Mar 22.

DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity

Shiwei Song  1 , Zachary F Pursell, William C Copeland, Matthew J Longley, Thomas A Kunkel, Christopher K Mathews
Affiliations

DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity

Shiwei Song et al. Proc Natl Acad Sci U S A. .

Abstract

The mutation rate of the mammalian mitochondrial genome is higher than that of the nuclear genome. Because mitochondrial and nuclear deoxyribonucleoside triphosphate (dNTP) pools are physically distinct and because dNTP concentrations influence replication fidelity, we asked whether mitochondrial dNTP pools are asymmetric with respect to each other. We report here that the concentrations of the four dNTPs are not equal in mitochondria isolated from several tissues of both young and old rats. In particular, in most tissues examined, mitochondrial dGTP concentrations are high relative to the other dNTPs. Moreover, in the presence of the biased dNTP concentrations measured in heart and skeletal muscle, the fidelity of DNA synthesis in vitro by normally highly accurate mtDNA polymerase gamma is reduced, with error frequencies increased by as much as 3-fold, due to increased formation of template T.dGTP mismatches that are inefficiently corrected by proofreading. These data, plus some published data on specific mitochondrial mutations seen in human diseases, are consistent with the hypothesis that normal intramitochondrial dNTP pool asymmetries may contribute to spontaneous mutagenesis in the mammalian mitochondrial genome.

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Figures

Fig. 1.
Fig. 1.
Relative error rates for T to C substitutions by pol γ with varying dNTP pools. Wild-type and exonuclease-deficient pol γ were used to fill M13mp2-gapped DNA as described in Materials and Methods by using the dNTP concentrations indicated in Table 1. Error rates were calculated from the data in Tables 2 and 3 (as described in ref. 31) for all T to C changes and for T(C) to C changes for T having template C as a 5′neighbor. The values plotted are rates relative to error rates observed by using 1 μM of each of the four dNTPs, which were assigned a value of 1. For exonuclease-deficient pol γ, the actual rates are 2.1 × 10–5 and 3.0 × 10–5 for T to C and T(C) to C errors, respectively. For wild-type pol γ, the actual rates are 0.64 × 10–5 and 1.1 × 10–5 for T to C and T(C) to C errors, respectively. *, theoretical value if at least one mutant plaque had been detected. SM, skeletal muscle.
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