Simulations of mitochondrial fusion-fission with neutral mutations.

<p>The simulations were done in triplicate and the error bars show the standard deviation. (A) The COV of R_M^cell increases at a slower rate with decreasing mixing time constant (i.e. faster fusion-fission). (B) The inhibition of fusion or fission and slower fusion-fission lead to an increase in the rate at which cells reach 80% mutation level. Simulations were performed with an initial R_M^cell of 10% mutation load in the presence of mtDNA turnover.</p

Ranking of mitochondrial QC processes by global sensitivity analysis.

<p>Ranking of mitochondrial QC processes by global sensitivity analysis.</p

Deletion breakpoints and direct repeats.

<p>Distributions of left and right breakpoints of aging-associated mtDNA deletions and of left and right DR motifs from (A) human, (B) rhesus monkey, (C) mouse and (D) rat. Standard deviation (error bars) for the frequency of breakpoints in each bin is calculated based on a binomial distribution.</p

Appearance and disappearance of mutant-rich mitochondria.

<p>The simulations were performed with only mitochondrial fusion-fission process and with non-selective fusion, for (A) <i>τ</i> = 7.5 days and (B) <i>τ</i> = 30 days.</p

Simulations of mitochondrial fusion-fission with deleterious mutations.

<p>The simulations were done in triplicate and the error bars show the standard deviation. (A) Inhibiting fusion or fission separately and slowing down fusion-fission quicken the accumulation of total mutation burden. (B) Similarly, the rate at which cells reach 80% mutation level increases with slower fusion-fission mixing of nucleoids. However, for the same mixing time constant, retrograde signalling reduces the rate at which cell undergo clonal expansion. Simulations were performed with an initial R_M^cell of 10%.</p

Abundance of stem-loop motifs in mtDNA and random DNA sequences.

<p>Abundance of stem-loop motifs in mtDNA and random DNA sequences.</p

Pseudo-code of the stochastic simulation algorithm implementation of the present model.

<p>Pseudo-code of the stochastic simulation algorithm implementation of the present model.</p

Free energy and position wise distribution of the DRs in mtDNA major arc.

<p>Resolution of DR distribution based on DR free energy and position in mtDNA sequence of (A) human, (B) rhesus monkey, (C) mouse and (D) rat. The x- and y- axis values denote the midpoint of each corresponding bin, i.e. a bin centered at 5.5 kb denotes a range from 5 to 6 kb and similarly, a bin centered at −2 kcal/mol has a range between 0 to −4 kcal/mol. (E) The most stable DR motifs in mtDNA major arc are associated with reported common deletions. Left and right breakpoint positions (denoted by open and close braces respectively) of common deletion <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035271#pone.0035271-Shoffner1" target="_blank">[18]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035271#pone.0035271-Edris1" target="_blank">[27]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035271#pone.0035271-Lee1" target="_blank">[28]</a>, the flanking DR sequence (highlighted in red) and the calculated DR free energy value in human, rhesus monkey and rat mtDNA.</p

Nominal model parameter values.

<p>Nominal model parameter values.</p

Model simulations with and without selectivity in mitochondrial fusion.

<p>(A & B) Model simulations under two different mixing time constants (<i>τ</i> = 7.5 and 30 days) for (A) mutations without RA and (B) mutations with RA (<i>k</i>_<i>R</i> = 2). (C & D) Model simulations of non-selective fusion for (C) mutations without RA and (D) with RA. The error bars represent the standard deviation of </p><p></p><p></p><p></p><p></p><p><mi>R</mi><mo>¯</mo></p><mi>M</mi><p><mi>C</mi><mi>e</mi><mi>l</mi><mi>l</mi></p><p></p><p><mo>(</mo><mi>t</mi><mo>)</mo></p><p></p><p></p><p></p> among 10,000 cells.<p></p