FIGURE 4.

Metabolic landscape of the vertebrate outer retina. Representation of known metabolic interactions of cells within the outer retina. Glucose from the choroidal blood supply transverses the endothelium and enters the RPE via GLUT1. In the RPE, glucose flows through the cell un-metabolized, thus reaching the basal membrane adjacent to PhR OS. Glucose leaves the RPE via GLUT1 into the PhR layer. PhRs take up glucose via GLUT1 and use it to fuel aerobic glycolysis. Aerobic glycolysis in PhRs fuels the PPP, creating nucleic acids and offsetting ROS production from mitochondrial activity, and creates DHAP which is used to synthesize phospholipids necessary to create OS disks thus driving OS growth and PhR function. Lactate from aerobic glycolysis is transported from PhRs to the extracellular space where it is taken up by other cells such as MGC and RPE, fueling TCA cycle and OXPHOS in these cells. RPE cells take up lactate and transform into pyruvate, which enters the TCA. This LDHB activity depletes available NAD⁺, effectively inhibiting glycolysis, allowing glucose to reach GLUTs in the basal RPE membrane. Extending OS tips externalize PS and contact with RPE projections and subsequent phagocytosis leads to Akt activation, which also downregulates glycolysis in these cells. PhR OS phagocytosis in the RPE leads to an increase in available fatty acids from breaking down the membranous lipid disks. These fatty acids undergo β-oxidation creating ketone bodies in the form of β-hydroxybutyrate, which can be further metabolized and used in the TCA cycle, supplementing RPE mitochondrial activity. Both fatty acids and ketone bodies are transported to the PhR layer where they are taken up by these and used to supplement TCA cycle and OXPHOS. A reciprocal malate-succinate shuttle between PhRs and RPE cells exists that exchanges reducing power between these cells. In PhR, reverse SDH activity, due to hypoxia-induced decrease of COXIV, produces succinate that is exported to RPE cells, where it is oxidized in the TCA cycle and generates a surplus of malate. Malate is then exported to the PhR layer, enters the TCA cycle and fuels succinate production. Rods effectively promote cone survival and function by secreting RdCVF, which binds and makes a complex with BSG1 and GLUT1 in the cone membrane, promoting glucose supply to these cells. Abbreviations: ADP, adenosine diphosphate; Akt, protein kinase B; ATP, adenosine triphosphate; BSG1, basigin 1; COXIV, cytochrome c oxidase subunit 4; DHAP, dihydroxyacetone phosphate; Glc, glucose; GLUT, glucose transporter; Lac, lactate; LDH, lactate dehydrogenase; Mal, malate; MCT, monocarboxylate transporter; MGC, Müller glia cell; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide, reduced; OS, outer segment; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PhR, photoreceptor; PPP, pentose phosphate pathway; PS, phosphatidylserine; Pyr, pyruvate; RdCVF, rod-derived cone viability factor; ROS, reactive oxygen species; RPE, retinal pigment epithelium; SDH, succinate dehydrogenase; Suc, succinate; TCA, tricarboxylic acid.