Retinal Function and Structure in Ant1-Deficient Mice

Mitochondrial metabolism is the primary source of aerobic energy generated by the transport of electrons into a chemiosmotic gradient across the inner membrane of the mitochondria. This complex process, called oxidative phosphorylation (OXPHOS), results in the production of adenosine triphosphate (ATP) within the mitochondria. ATP enters the cytosol through an exchange with ADP by way of adenine nucleotide translocator (ANT), which resides in the inner mitochondrial membrane.1 ANT is expressed in mammals as four isoforms (ANT1, ANT2, ANT3, and ANT4) with varying degrees of tissue specificity.2,3 A transgenic mouse lacking Ant1 has been generated that exhibits a loss of mitochondrial ATP.4 As expected, this loss of ATP leads to mitochondrial proliferation in cardiac and skeletal muscle, as evidenced by increased histochemical staining for the mitochondrial enzymes cytochrome c oxidase (COX) and succinate dehydrogenase (SDH), and cardiac hypertrophy. In addition, the absence of Ant1 inhibits OXPHOS, creating an increase in reactive oxygen species and mitochondrial DNA (mtDNA) mutations in the Ant1−/− mice with age.5 Thus, the Ant1−/− mouse has been identified as a mouse model of mitochondrial myopathy and cardiomyopathy.4 The retina is one of the most metabolically active tissues in the body, with abundant mitochondria found in the photoreceptors and retinal pigment cells.6 Given these high metabolic needs, retinal degeneration and visual deficits would seem likely when there is mitochondrial dysfunction. However, the most common ocular defect associated with mitochondrial myopathy is ophthalmoplegia, followed by optic neuropathy and pigmentary retinopathy,7,8 all fairly rare diseases. Pigmentary retinopathy is most often seen in a subset of patients with chronic progressive external ophthalmoplegia, called Kearns-Sayre Syndrome, and in patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and MNGIE (mitochondrial neurogastrointestinal encephalomyopathy). Retinopathy in these conditions, though mainly involving the retinal pigment epithelium, is phenotypically variable and often subclinical.9 Mutations in ANT1 are linked to autosomal dominant external ophthalmoplegia (adPEO).10–13 Our previous studies have shown Ant1−/− mice to be a pathologic model of adPEO.14 The mice have been established as a model of mitochondrial myopathy and cardiomyopathy,4 but retinal function and morphology have not been reported. To determine the role of ANT1 in the retina, retinal function and structure were examined in the Ant1−/− mouse.