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.

Symbiotic relationships between neurons and glia must adapt to structures, functions, and metabolic roles of the tissues they are in. We show here that Müller glia in retinas have specific enzyme deficiencies that can enhance their ability to synthesize Gln. The metabolic cost of these deficiencies is that they impair the Müller cell's ability to metabolize Glc. We show here that the cells can compensate for this deficiency by using metabolites produced by neurons. Müller glia are deficient for pyruvate kinase (PK) and for aspartate/glutamate carrier 1 (AGC1), a key component of the malate-aspartate shuttle. In contrast, photoreceptor neurons express AGC1 and the M2 isoform of pyruvate kinase, which is commonly associated with aerobic glycolysis in tumors, proliferating cells, and some other cell types. Our findings reveal a previously unidentified type of metabolic relationship between neurons and glia. Müller glia compensate for their unique metabolic adaptations by using lactate and aspartate from neurons as surrogates for their missing PK and AGC1.glutamine metabolism | aerobic glycolysis | retina | Müller glia | photoreceptors A erobic glycolysis is a metabolic adaptation that proliferating cells use to meet anabolic demands (1, 2). In tumors, it is called the "Warburg effect." Tumors convert ∼90% of Glc they consume to lactate (Lac). The brain converts only 2-25% of the Glc it uses to Lac (3).In retinas of vertebrate animals, energy is produced in a way that resembles tumor metabolism more than brain metabolism. Aerobic glycolysis accounts for 80-96% of Glc used by retinas (4-7). Retinas are made up of neurons and glia (8). The outermost layer is occupied by photoreceptors (PRs). The inner layers are a diverse collection of signal processing neurons. Müller glia spans the thickness of the retina. The site of aerobic glycolysis in retina has not been established.Exchange of fuels is an important part of the relationship between neurons and glia (9-12). Transfer of metabolites between intracellular compartments also is important. Glycolysis is supported by reoxidation of cytosolic NADH, which can be catalyzed by lactate dehydrogenase (LDH) or by the malate-aspartate shuttle (MAS). PRs and other neurons in retinas express aspartate/glutamate carrier 1 (AGC1; also known as "Aralar") (13), a mitochondrial aspartate/glutamate carrier that has a key role in the MAS. However, Müller cells (MCs) are AGC1-deficient (13). The significance of the distribution of AGC1 has been enigmatic.Aerobic metabolism in tumors is linked to expression of the M2 isoform of pyruvate kinase, PKM2 (14, 15). Pyruvate kinase (PK) catalyzes the final step in glycolysis, synthesis of Pyr (16). Liver (PKL) and erythrocyte (PKR) isoforms are splice variants of the PKLR gene, and PKM1 and PKM2 are splice variants of the PKM gene. A unique feature of PKM2 is that it is responsive to allosteric and posttranslational regulators (16). PKM2 expression in cancer cells correlates with reduced yield of ATP from Glc and accumulation of glycolytic inte...

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.