Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy

Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy caused by <i>OPA1</i> variants, leading to retinal ganglion cell (RGC) degeneration and vision loss. The mechanisms behind RGC vulnerability to mitochondrial dysfunction remain unclear. We developed a patient-specific <i>Opa1^V291D/+</i> knock-in mouse model to investigate mitochondrial dysfunction and retinal metabolism in ADOA. We observed that <i>Opa1^V291D/+</i> mice exhibited anatomical and functional RGC abnormalities recapitulating the ADOA phenotypes. Reduced optic atrophy 1 (OPA1) protein levels were noted in <i>Opa1^V291D/+</i> mice, accompanied by decreased protein stability. Moreover, mitochondrial function was compromised, as indicated by reduced Complex I activity, increased oxidative stress, and diminished adenosine triphosphate production in the retinas of <i>Opa1^V291D/+</i> mice. Spatial metabolomics revealed energy deficits in the inner retina and heightened glycolysis in the outer retina. Immunostaining showed decreased expression of glycolytic proteins in the ganglion cell layer. Single-nucleus RNA sequencing disclosed significant down-regulation of energy-production genes in RGCs, while other retinal cell types remained unaffected. These findings emphasize the specific vulnerability of RGCs to bioenergetic crises, connecting disrupted energy homeostasis to their degeneration. By increasing the nicotinamide adenine dinucleotide (NAD⁺)/reduced form of NAD⁺ (NADH) redox ratio through the overexpression of mitochondrial-targeted <i>Lactobacillus brevis</i> NADH oxidase (<i>MitoLbNOX</i>) in RGCs, we demonstrated improved RGC function and survival through enhanced energy metabolism and reduced oxidative stress. These findings confirm that disrupted energy metabolism leads to RGC degeneration and emphasize the enhancement of the NAD⁺/NADH redox ratio as a promising treatment strategy to protect RGCs from degeneration in ADOA.