OPA1 gene and mitochondrial optic neuropathy: disease mechanisms and potential therapies

Summary Primary inherited optic neuropathies are a group of blinding genetic disorders in which optic atrophy secondary to loss of retinal ganglion cells is a key clinical feature. The commonest causes world‐wide are mutation in mitochondrial DNA (causing Leber's Hereditary Optic Neuropathy) and mutation in the nuclear gene, OPA1 (causing Autosomal Dominant Optic Atrophy: ADOA). 60–75% of patients with autosomal dominant optic atrophy have mutations in the OPA1 gene. The OPA1 protein is targeted to the mitochondria and is involved in regulation of mitochondrial fusion. A better understanding of mitochondrial function, including dynamics, is revealing that functional and structural changes in mitochondrial morphology are important factors in diseases of ageing in the eye and visual system. Key proteins have been discovered which control the balance of mitochondrial fusion and fission and have a range of other functions, such as controlling maintenance of mitochondrial DNA, cell death, autophagy, mitochondrial metabolism and redox signalling. A decline in mitochondrial function plays a role in the ageing process and increases the incidence of age‐related disorders. Mitochondrial optic neuropathies are ‘orphan’ diseases but with the advent of recent trials of novel therapies in patients with the mitochondrial optic neuropathy, Leber's hereditary optic neuropathy, there is the first glimmer of hope for the treatment of this group of patients.