Early embryonic and NCR mtDNA mutations in <i>Polg</i> mice.

<p>(A) Bar graphs representing changes in mean heteroplasmy of early embryonic mutations with <i>Polg</i> mice aging. Error Bars, mean ± SEM. (B) Distribution of non-synonymous early embryonic mtDNA mutations among different genes. Error bars, mean ± SEM. (C) Quantification of mtDNA mutations in the non-coding region (NCR) in <i>Polg</i> mice (n = 12 for 2 months; n = 24 for 9 months). Error bars, mean ± SEM. (D) Bar graphs representing mean heteroplasmy levels of NCR mtDNA mutations in <i>Polg</i> mice with aging. Error bars, mean ± SEM. (E) Summary of mtDNA mutations found in the NCR region (mtDNA15423-16299) in <i>Polg</i> mice. Dots represent mtDNA mutations and numbers under dots represent the heteroplasmy levels. ETAS indicates the extended termination associated sequence and CSB indicates the conserved sequence block.</p

Summary of mtDNA mutations detected in wild type and <i>Polg</i> mice.

<p>Summary of mtDNA mutations detected in wild type and <i>Polg</i> mice.</p

Characterization of mtDNA mutations in wild type mice with aging.

<p>(A) Quantification of mtDNA mutations (mean ± SEM; asterisk, P < 0.05, Student’s t-test) for different mutation types in young wt mice at age 2–13 months (green bars; n = 31) and old mice at age 18–34 months (orange bars; n = 44). Somatic mutations were undetectable in wt mice. Asterisk represents a significant increase in number of germline mutations with age. (B) Mean heteroplasmy levels of non-synonymous germline and early embryonic mutations as a function of age. Error bars, mean ± SEM. Asterisk represents a significant increase in the mean heteroplasmy levels of non-synonymous germline mutations in old wt mice compared to the young group (P < 0.05, Student’s t-test). (C) Pie chart showing gene distribution of non-synonymous germline mutations in protein-coding and RNA coding genes in old wt mice. (D) Bar graphs showing mean heteroplasmy levels for non-synonymous germline mutations in protein-coding and RNA-coding genes in old wt mice. (E) Heteroplasmy of non-synonymous mutations in protein-coding and RNA-coding genes of early embryonic origin. (F) Pie chart showing relative proportion of mutation types in young and old wt mice. (G) Mitochondrial OXPHOS complex I activity in iPS cells carrying non-synonymous mutations in protein-coding genes and in age-matched control ESCs or iPS cells. The complex I activity was measured in cell homogenates (n = 12 per cell line, technical replicates) and was expressed as “% rotenone inhibition”. 10m-iPS7, 34m-iPS9 and 34m-iPS10 cells displayed reduced activities compared to controls. (H) Mitochondrial OXPHOS complex IV activity in iPS cells carrying non-synonymous mutations in protein-coding genes and in age-matched control ES or iPS cells. The complex IV activity was measured in cell homogenates (n = 12 per cell line, technical replicates) and was expressed as “nmol / min / mg protein”. 18m-iPS2 cells showed decreased activity compared to controls. In (G and H), ns denotes p ≥ 0.05.</p