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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 43; pp. 15579 - 15584
• Main Authors: Lindsay, Ken J., Du, Jianhai, Sloat, Stephanie R., Contreras, Laura, Linton, Jonathan D., Turner, Sally J., Sadilek, Martin, Satrústegui, Jorgina, Hurley, James B.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.10.2014; National Acad Sciences
• Subjects: Amino Acid Transport Systems, Acidic - metabolism; Animals; Antiporters - metabolism; Aspartic Acid - metabolism; Biological Sciences; Brain; Carbon Isotopes; Cells; Cells, Cultured; Cellular metabolism; Citrates; Enzymes; Ependymoglial Cells - metabolism; Ependymoglial Cells - radiation effects; Gin; Glucose - metabolism; Glutamine - metabolism; Glycolysis; HeLa Cells; Humans; Isoenzymes - metabolism; Kinases; Lactose - metabolism; Light; Metabolites; Mice; Models, Biological; Neuroglia; Neuroglia - metabolism; Neuroglia - radiation effects; Neurons; Oxidation-Reduction - radiation effects; Photoreceptor Cells, Vertebrate - metabolism; Photoreceptor Cells, Vertebrate - radiation effects; Protein isoforms; Pyruvate Kinase - metabolism; Retina; Retinal Neurons - metabolism; Retinal Neurons - radiation effects; Tumors; glutamine metabolism; photoreceptors; Müller glia; retina; aerobic glycolysis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1412441111

Symbiotic relationships between neurons and glia must adapt to structures, functions, and metabolic roles of the tissues they are in. We show here that Múííóóóéíóéóüüüller 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 Múííóóóéíóéóüüüüller cell’s ability to metabolize Glc. We show here that the cells can compensate for this deficiency by using metabolites produced by neurons. Múííóóóéíóéóüüüüüller 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. Múííóóóéíóéóüüüüüüller glia compensate for their unique metabolic adaptations by using lactate and aspartate from neurons as surrogates for their missing PK and AGC1. Significance Aerobic glycolysis is a metabolic adaptation that helps cells in a tumor meet high anabolic demands. The M2 isoform of pyruvate kinase (PKM2) is associated with aerobic glycolysis in cancer cells. Aerobic glycolysis also accounts for most of the Glc metabolized in retinas. We find that photoreceptors (PRs) in retinas, like cancer cells in tumors, express PKM2. We also found very little expression of pyruvate kinase (PK) in Múííóóóéíóéóüller glia. We present metabolic flux analyses that show a metabolic relationship between PRs and Múííóóóéíóéóüüller cells (MCs) that is different from the relationship between some neurons and astrocytes in brain. To compensate for PK deficiency and aspartate/glutamate carrier 1 deficiencies, MCs can fuel their mitochondria with lactate and aspartate produced by PRs.