Subtle changes in the neural retina can be detected much earlier than retinal vasculopathy in diabetic retinopathy. In mice fed a high fat diet, we have found early and progressive decline in visual acuity, as measured by optokinetic tracking, even before significant weight gain and hyperglycemia. Fundus examination was normal and fluorescein angiography showed normal retinal vasculature. The only major histologic findings were swollen mitochondria, edema and degenerative changes in the retinal pigment epithelium (RPE). Outer retinal ischemia and inflammation are supported by elevated VEGF, TNFa, MCP-1, and choroidal neovascular tufts. Treatment with a mitochondria-targeted tetrapeptide (SS-31/MTP-131) reversed visual decline without reducing blood glucose, body weight or insulin resistance. SS-31 is known to target cardiolipin and promote electron transfer and ATP synthesis. SS-31 preserved mitochondrial morphology and integrity of the RPE, reduced inflammatory markers, and prevented choroidal neovascularization. These results demonstrate a causal relationship between RPE mitochondrial energy failure and loss of visual acuity in early metabolic syndrome, and support a bioenergetics-based approach for preventing diabetic complications. A topical formulation of SS-31 (OcuviaTM) is in Phase 2 clinical trial for diabetic macula edema and non-proliferative age-related macular degeneration.