title: Brain glutamine synthesis requires neuronal-born aspartate as amino donor for glial glutamate formation.
abstract: The glutamate-glutamine cycle faces a drain of glutamate by oxidation, which is balanced by the anaplerotic synthesis of glutamate and glutamine in astrocytes. De novo synthesis of glutamate by astrocytes requires an amino group whose origin is unknown. The deficiency in Aralar/AGC1, the main mitochondrial carrier for aspartate-glutamate expressed in brain, results in a drastic fall in brain glutamine production but a modest decrease in brain glutamate levels, which is not due to decreases in neuronal or synaptosomal glutamate content. In vivo (13)C nuclear magnetic resonance labeling with (13)C(2)acetate or (1-(13)C) glucose showed that the drop in brain glutamine is due to a failure in glial glutamate synthesis. Aralar deficiency induces a decrease in aspartate content, an increase in lactate production, and lactate-to-pyruvate ratio in cultured neurons but not in cultured astrocytes, indicating that Aralar is only functional in neurons. We find that aspartate, but not other amino acids, increases glutamate synthesis in both control and aralar-deficient astrocytes, mainly by serving as amino donor. These findings suggest the existence of a neuron-to-astrocyte aspartate transcellular pathway required for astrocyte glutamate synthesis and subsequent glutamine formation. This pathway may provide a mechanism to transfer neuronal-born redox equivalents to mitochondria in astrocytes.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, and CIBER de Enfermedades Raras, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
authors.forename: Tiago B
authors.initials: TB
authors.lastname: Rodrigues
authors.forename: Laura
authors.initials: L
authors.lastname: Contreras
authors.forename: Miguel
authors.initials: M
authors.lastname: Garzón
authors.forename: Irene
authors.initials: I
authors.lastname: Llorente-Folch
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.forename: Sebastian
authors.initials: S
authors.lastname: Cerdan
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
mesh_terms: D000409:Alanine / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000096:biosynthesis*; D005973:Glutamine / Q000096:biosynthesis*; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009474:Neurons / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005973:Glutamine; D001224:Aspartic Acid; D019344:Lactic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D019289:Pyruvic Acid; D007930:Leucine; D005947:Glucose; D009584:Nitrogen; D000409:Alanine