Pathogenic OPA1 mutations cause
autosomal dominant optic atrophy (DOA), a condition characterized by the preferential loss of retinal ganglion cells and progressive optic nerve degeneration. Approximately 20% of affected patients will also develop more severe neuromuscular complications, an important disease subgroup known as DOA(+).
Cytochrome c oxidase (COX)-negative fibres and multiple
mitochondrial DNA (
mtDNA) deletions have been identified in skeletal muscle biopsies from patients manifesting both the pure and syndromal variants, raising the possibility that the accumulation of somatic
mtDNA defects contribute to the disease process. In this study, we investigated the
mtDNA changes induced by OPA1 mutations in skeletal muscle biopsies from 15 patients with both pure DOA and DOA(+) phenotypes. We observed a 2- to 4-fold increase in
mtDNA copy number at the single-fibre level, and patients with DOA(+) features had significantly greater
mtDNA proliferation in their COX-negative skeletal muscle fibres compared with patients with isolated
optic neuropathy. Low levels of wild-type
mtDNA molecules were present in COX-deficient muscle fibres from both pure DOA and DOA(+) patients, implicating haplo-insufficiency as the mechanism responsible for the biochemical defect. Our findings are consistent with the 'maintenance of wild-type' hypothesis, the secondary
mtDNA deletions induced by OPA1 mutations triggering a compensatory mitochondrial proliferative response in order to maintain an optimal level of wild-type
mtDNA genomes. However, when deletion levels reach a critical level, further mitochondrial proliferation leads to replication of the mutant species at the expense of wild-type
mtDNA, resulting in the loss of respiratory chain COX activity.