Fig 1.
Mitochondrial quality control processes.
The model accounts for the processes of mitochondrial turnover (mitogenesis and mitophagy) and mitochondrial fusion-fission. The box highlights the selectivity of mitochondrial fusion and mitophagy. Mitochondria with a high fraction of mutant mtDNA and consequently lowered membrane potential (Δψ) are less likely to fuse with other mitochondria and preferentially removed by mitophagy.
Fig 2.
Detailed model implementation.
(A) Partitioning of the 2D circular cell in the model. (B) OXPHOS defect function . (C) Schematic diagram of model implementation of mitochondrial turnover and fusion-fission (see text for detailed explanation). (D) Steady state distribution of mitochondrial nucleoid contents. The inset shows the fission propensity as a function of mitochondrial nucleoid content. (E) Nucleoids mixing time. Mitochondrial heterogeneity in each cell is represented by the mean coefficient of variation (COV) of RMmito. The mean COV of RMmito is scaled such that the steady state value is −100%. The results come from simulating only mitochondrial fusion-fission (without mitochondrial turnover) for 10,000 cells.
Table 1.
Nominal model parameter values.
Table 2.
Range of parameter values for global sensitivity analysis.
Table 3.
Ranking of mitochondrial QC processes by global sensitivity analysis.
Fig 3.
Model simulations with and without selectivity in mitochondrial fusion.
(A & B) Model simulations under two different mixing time constants (τ = 7.5 and 30 days) for (A) mutations without RA and (B) mutations with RA (kR = 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 among 10,000 cells.
Fig 4.
High selectivity in mitochondrial fusion and mitophagy providing efficient removal of mutant mDNA.
(A & B) Model simulations with high mitophagy selectivity (rD,max = 199) and non-selective fusion for (A) mutations without RA and (B) with RA (kR = 2). (C & D) Model simulations with high fusion selectivity (rfusi,max = 100%, rD,max = 5) for (C) mutations without RA and (D) with RA. The error bars represent the standard deviation of among 10,000 cells.
Fig 5.
Appearance and disappearance of mutant-rich mitochondria.
The simulations were performed with only mitochondrial fusion-fission process and with non-selective fusion, for (A) τ = 7.5 days and (B) τ = 30 days.
Fig 6.
Effects of lower selectivity of mitochondrial fusion and mitophagy.
Model simulations were performed by lowering the mitophagy selectivity (rD,max) and fusion selecitivity (rfusi,max) to half (50%) of the nominal values, for mutant mtDNA molecules (A) with RA (kR = 2) and (B) without RA. The error bars show the standard deviation of among 10,000 cells.