title: Down-regulation of the mitochondrial aspartate-glutamate carrier isoform 1 AGC1 inhibits proliferation and N-acetylaspartate synthesis in Neuro2A cells.
abstract: The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) catalyzes a Ca2+-stimulated export of aspartate to the cytosol in exchange for glutamate, and is a key component of the malate-aspartate shuttle which transfers NADH reducing equivalents from the cytosol to mitochondria. By sustaining the complete glucose oxidation, AGC1 is thought to be important in providing energy for cells, in particular in the CNS and muscle where this protein is mainly expressed. Defects in the AGC1 gene cause AGC1 deficiency, an infantile encephalopathy with delayed myelination and reduced brain N-acetylaspartate (NAA) levels, the precursor of myelin synthesis in the CNS. Here, we show that undifferentiated Neuro2A cells with down-regulated AGC1 display a significant proliferation deficit associated with reduced mitochondrial respiration, and are unable to synthesize NAA properly. In the presence of high glutamine oxidation, cells with reduced AGC1 restore cell proliferation, although oxidative stress increases and NAA synthesis deficit persists. Our data suggest that the cellular energetic deficit due to AGC1 impairment is associated with inappropriate aspartate levels to support neuronal proliferation when glutamine is not used as metabolic substrate, and we propose that delayed myelination in AGC1 deficiency patients could be attributable, at least in part, to neuronal loss combined with lack of NAA synthesis occurring during the nervous system development.
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Profilo
authors.affiliation: Department of Pharmacy and BioTechnology, University of Bologna, Bologna 40126, Italy.
authors.forename: Luis Emiliano
authors.initials: LE
authors.lastname: Peña-Altamira
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Corricelli
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castegna
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Danese
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Agrimi
authors.affiliation: Department of Pharmacy and BioTechnology, University of Bologna, Bologna 40126, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Petralla
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Giannuzzi
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Porcelli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Sbano
authors.affiliation: MRC-Mitochondrial Biology Unit, Cambridge, UK; Fondazione IRCCS Istituto Neurologico "C. Besta", Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.affiliation: Department of Pharmacy and BioTechnology, University of Bologna, Bologna 40126, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Massenzio
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy.
authors.forename: Erika Mariana
authors.initials: EM
authors.lastname: Palmieri
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiermonte
authors.affiliation: Department of Pharmacy and BioTechnology, University of Bologna, Bologna 40126, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Virgili
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy; Institute of Biomembranes and Bioenergetics, Consiglio Nazionale delle Ricerche, Bari 70126, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Palmieri
authors.affiliation: MRC-Mitochondrial Biology Unit, Cambridge, UK; Fondazione IRCCS Istituto Neurologico "C. Besta", Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Pharmacy and BioTechnology, University of Bologna, Bologna 40126, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Monti
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Bari 70125, Italy; Institute of Biomembranes and Bioenergetics, Consiglio Nazionale delle Ricerche, Bari 70126, Italy. Electronic address: ferdinando.palmieri@uniba.it.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.affiliation: Institute of Biomembranes and Bioenergetics, Consiglio Nazionale delle Ricerche, Bari 70126, Italy. Electronic address: fm.lasorsa@ibbe.cnr.it.
authors.forename: Francesco Massimo
authors.initials: FM
authors.lastname: Lasorsa
mesh_terms: D026905:Amino Acid Transport Systems / Q000096:biosynthesis*; D026922:Amino Acid Transport Systems, Acidic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017920:Antiporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011596:Psychomotor Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D026905:Amino Acid Transport Systems; D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; D024101:Mitochondrial Proteins; C486757:SLC7A13 protein, human; D001224:Aspartic Acid; C000179:N-acetylaspartate
keywords: AGC1 deficiency; Brain hypomyelination; Mitochondrial aspartate/glutamate carrier; N-Acetylaspartate synthesis; Neurodegenerative disorders