Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina

Abstract

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...

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

“…hCardiac ECs were obtained from Lonza and cultured according to the manufacturer's protocol. Müller glial cells were isolated from mice as reported (58) and cultured in Neurobasal medium with 10% (vol/vol) FBS.…”

Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development

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