Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss.

1Here we report multiple lines of evidence for a comprehensive model for retinal 2 energy metabolism. Metabolic flux, locations of key enzymes and our finding that 3 glucose enters the neural retina almost entirely through photoreceptors support a 4 conceptually new model for retinal metabolism. In this model, glucose from the 5 choroidal blood supply passes through the retinal pigment epithelium to the retina 6 where photoreceptors convert it to lactate. Photoreceptors then export the lactate 7 as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. A 8 key feature of this model is that aerobic glycolysis in photoreceptors produces 9 lactate to suppress glycolysis in the neighboring retinal pigment epithelium. That 10 enhances the flow of glucose to the retina by minimizing consumption of glucose 11 within the retinal pigment epithelium. This framework for metabolic relationships 12 in retina provides new insights into the underlying causes of retinal disease, age-13 related vision loss and metabolism-based therapies.

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Ca2ϩ ions have distinct roles in the outer segment, cell body, and synaptic terminal of photoreceptors. We tested the hypothesis that distinct Ca 2ϩ domains are maintained by Ca 2ϩ uptake into mitochondria. Serial block face scanning electron microscopy of zebrafish cones revealed that nearly 100 mitochondria cluster at the apical side of the inner segment, directly below the outer segment. The endoplasmic reticulum surrounds the basal and lateral surfaces of this cluster, but does not reach the apical surface or penetrate into the cluster. Using genetically encoded Ca 2ϩ sensors, we found that mitochondria take up Ca 2ϩ when it accumulates either in the cone cell body or outer segment. Blocking mitochondrial Ca 2ϩ uniporter activity compromises the ability of mitochondria to maintain distinct Ca 2ϩ domains. Together, our findings indicate that mitochondria can modulate subcellular functional specialization in photoreceptors.