title: AGC1/2, the mitochondrial aspartate-glutamate carriers.
abstract: In this review we discuss the structure and functions of the aspartate/glutamate carriers (AGC1-aralar and AGC2-citrin). Those proteins supply the aspartate synthesized within mitochondrial matrix to the cytosol in exchange for glutamate and a proton. A structure of an AGC carrier is not available yet but comparative 3D models were proposed. Moreover, transport assays performed by using the recombinant AGC1 and AGC2, reconstituted into liposome vesicles, allowed to explore the kinetics of those carriers and to reveal their specific transport properties. AGCs participate to a wide range of cellular functions, as the control of mitochondrial respiration, calcium signaling and antioxydant defenses. AGC1 might also play peculiar tissue-specific functions, as it was found to participate to cell-to-cell metabolic symbiosis in the retina. On the other hand, AGC1 is involved in the glutamate-mediated excitotoxicity in neurons and AGC gene or protein alterations were discovered in rare human diseases. Accordingly, a mice model of AGC1 gene knock-out presented with growth delay and generalized tremor, with myelinisation defects. More recently, AGC was proposed to play a crucial role in tumor metabolism as observed from metabolomic studies showing that the asparate exported from the mitochondrion by AGC1 is employed in the regeneration of cytosolic glutathione. Therefore, given the central role of AGCs in cell metabolism and human pathology, drug screening are now being developed to identify pharmacological modulators of those carriers. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
authors.affiliation: Univ. Bordeaux, U1211, Bordeaux, France; INSERM, U1211, Bordeaux, France; Instituto de Bioquímica Médica Leopoldo De Meis, UFRJ, Rio de Janeiro, Brazil.
authors.forename: N D
authors.initials: ND
authors.lastname: Amoedo
authors.affiliation: Univ. Bordeaux, U1211, Bordeaux, France; INSERM, U1211, Bordeaux, France; Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari.
authors.forename: G
authors.initials: G
authors.lastname: Punzi
authors.affiliation: Univ. Bordeaux, U1211, Bordeaux, France; INSERM, U1211, Bordeaux, France.
authors.forename: E
authors.initials: E
authors.lastname: Obre
authors.affiliation: Univ. Bordeaux, U1211, Bordeaux, France; INSERM, U1211, Bordeaux, France.
authors.forename: D
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari.
authors.forename: A
authors.initials: A
authors.lastname: De Grassi
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari. Electronic address: ciroleopierri@gmail.com.
authors.forename: C L
authors.initials: CL
authors.lastname: Pierri
authors.affiliation: Univ. Bordeaux, U1211, Bordeaux, France; INSERM, U1211, Bordeaux, France. Electronic address: rossig@u-bordeaux2.fr.
authors.forename: R
authors.initials: R
authors.lastname: Rossignol
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002417:Cattle; D016384:Consensus Sequence; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008293:Malates / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology; D009928:Organ Specificity; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D002135:Calcium-Binding Proteins; D008293:Malates; D033681:Mitochondrial Membrane Transport Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C114606:SLC25A12 protein, human; C491956:Slc25a12 protein, mouse; D009243:NAD; C008822:citrin; D001224:Aspartic Acid; D018698:Glutamic Acid; C030298:malic acid
keywords: AGC1; AGC2; Aralar; Aspartate; Calcium signaling; Cancer metabolism; Citrin; Energy metabolism; Glutamate; Malate-aspartate shuttle; Mitochondria; Neuron physiology; Rare diseases; Transport assays