Figure 5. Simulations of the effects of partial mitochondrial DNA (mtDNA) replication failure due to nucleoside analog (NRTI) exposure.

Using a validated computer model of mtDNA replication based solely on experimentally derived parameters ²², we incorporated a finite period of partial replication failure due to the mtDNA chain-terminating effects of NRTI exposure ⁹, assigning a probability of failure per mtDNA replication event. All other parameters remained constant, including the de novo mutation rate ²². 2000 cells were simulated for 80 years. (a) The amount of mtDNA depletion during the NRTI exposure period caused by 25% and 45% probability of replication failure between 20 and 30 years-of-age. (>50% failure led to the complete loss of mtDNA). The range of mtDNA depletion predicted is in keeping with published in vivo data^12,23. (b) This led to a persistent increase in the frequency of COX (cytochrome c oxidase) deficient cells through the accelerated clonal expansion of pre-existing somatic mtDNA mutations. (c) Direct simulation of the effects of NRTI exposure within our study population (two different periods, 10 and 3 years, starting at age 20, of replication failure with 45% probability). The range of COX defects predicted closely fits our empiric data. (d) Late exposure (40 – 50 years) had a more pronounced effect than early exposure (20 – 30 years) (with 45% probability of replication failure) due to the higher number of pre-existing (age-related) somatic mtDNA mutations at the time of exposure.