Degree of heteroplasmy reflects oxidant damage in a large family with the mitochondrial DNA A8344G mutation.

Mitochondria are the source of most oxygen-derived free radicals. Mutations in mitochondrial DNA can impair mitochondrial electron transport resulting in decreased ATP production and increased free radical-induced oxidant injury. The specific mitochondrial DNA mutation A8344G alters the TPsiC loop or the mitochondrial tRNA for lysine. We investigated a large five-generational family harboring this mutation to determine whether the degree of heteroplasmy (proportion of mutated mitochondrial genomes) for the mtA8344G mutation correlated with a marker of oxidant damage. We measured F2-isoprostanes because they are specific and reliable markers of oxidant injury formed when free radicals attack esterified arachidonate in cell membranes. Family members with high heteroplasmy (>40%) had significantly higher F2-isoprostane levels (62 +/- 39 pg/ml) than those with lower heteroplasmy (33 +/- 13 pg/ml, P < 0.001). The degree of heteroplasmy for the mtA8344G mutation in this family correlated positively with F2-isoprostane levels (P = 0.03). This study highlights the underappreciated role free radicals play in the complex pathophysiology of inherited mitochondrial DNA disorders. The most important novel finding from this family is that some currently asymptomatic individuals with moderate heteroplasmy have evidence of ongoing free-radical mediated oxidant injury.