OPA1 mutations induce mtDNA proliferation in leukocytes of patients with dominant optic atrophy

OPA1 mutations cause autosomal dominant optic atrophy (DOA), a debilitating mitochondrial optic neuropathy characterized by irreversible loss of retinal ganglion cells (RGCs) and progressive visual failure starting in early childhood.1 Interestingly, ∼20% of OPA1 carriers will develop a more severe form of the disease, DOA+, where the optic atrophy is compounded by additional neurologic features.1 OPA1 is a multifunctional mitochondrial inner membrane protein, and rather unexpectedly, high levels of cytochrome c oxidase (COX)-negative muscle fibers were recently identified in biopsy specimens from patients manifesting both the pure and syndromal phenotypes.2,3 These COX-negative muscle fibers harbored high levels of somatically acquired mitochondrial DNA (mtDNA) deletions and marked mtDNA proliferation was also observed, clearly revealing OPA1 to be a novel disorder of mtDNA maintenance.4 To further investigate this key pathologic mechanism, mtDNA copy number was quantified in blood leukocytes from 3 independent patient cohorts with molecularly confirmed OPA1 mutations.