mtDNA deletions in HET-CRE and HET hippocampus accumulate with age.

<p>Accumulation of mtDNA with deletions (average of deletions at the segments encoded for CYTB, COX3 and ND4) with age per single hippocampal cell from HET (white circles) and HET-CRE (black circles). The mtDNA deletions (represented as the mean ± SEM) values were fitted to a linear regression (equations shown in the figure) and the goodness of the regression was expressed as r². From the slope of each equation, the copy-error probability was estimated by using the following formulae N_del = (N_mtDNA*P_del*t * ln 2)/<i>t</i>_1/2, where N_del is the number of mtDNA with deletions, t is the age of mice in days throughout their lifetime (estimated as 2 years), N_mtDNA = 1,200 mtDNA copy number/cell (experimentally determined in hippocampus by evaluating the ratio of mitochondrial ND1 gene copy number to the nuclear PK gene copy number), and a mtDNA half-life (<i>t</i>_1/2) of 10 d <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042504#pone.0042504-Elson1" target="_blank">[121]</a>. For HET mice, a low copy-error probability was obtained (9.5×10⁻⁶) associated with a low incidence of accumulation of deletions with age, becoming more significant towards the end of their life. Higher copy-error probabilities, as that calculated with HET-CRE mice (1.9×10⁻⁵) lead to a greater accumulation of mtDNA with deletions throughout a simulated mouse life. A biochemical defect on CCO activity is evidenced when the level of a mtDNA deletion exceeds a critical threshold level of 50%–60% <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042504#pone.0042504-Hayashi1" target="_blank">[77]</a> (indicated with a dotted line).