How the most common mitochondrial DNA mutation (m.3243A>G) vanishes from leukocytes: a mathematical model

Mitochondrial diseases may be caused by alterations of the mitochondrial genome. The pathogenic variant m.3243A>G is one of the most frequent causes of mitochondrial disease and the most common mitochondrial DNA mutation. Patients with a variant in mitochondrial DNA can have a mixture of mutated and wild-type genomes (heteroplasmy). In the case of the pathogenic variant m.3243A>G, the degree of heteroplasmy (H) correlates to some extent with the severity of the disease. Several longitudinal studies, where H is measured at two different time-points, have shown an annual decline in leukocyte H values. Thus far, only an exponential decay of H with time has been noted but a mechanistic model is lacking. Here, I describe a deterministic mathematical model that accounts for the decline of H in leukocytes based on selective mechanisms acting at the stem cell level. The 'inverted-sigmoid' model provides estimates of at-birth H levels closer to those observed in post-mitotic tissues, such as skeletal muscle, than the estimates provided by an exponential decay. The new model never leads to predictions of H > 100% and provides a stronger correlation between at-birth H values in leukocytes and the scores of the Newcastle Mitochondrial Disease Scale for Adults, which can be of practical utility. This model could be extended to other mitochondrial DNA disease-causing variants.