Down-regulation of the mitochondrial aspartate-glutamate carrier isoform 1 AGC1 inhibits proliferation and N-acetylaspartate synthesis in Neuro2A cells

Emanuela Profilo, Luis Emiliano Peña-Altamira, Mariangela Corricelli, Alessandra Castegna, Alberto Danese, Gennaro Agrimi, Sabrina Petralla, Giulia Giannuzzi, Vito Porcelli, Luigi Sbano, Carlo Viscomi, Francesca Massenzio, Erika Mariana Palmieri, Carlotta Giorgi, Giuseppe Fiermonte, Marco Virgili, Luigi Palmieri, Massimo Zeviani, Paolo Pinton, Barbara MontiFerdinando Palmieri, Francesco Massimo Lasorsa

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1422-1435
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number6
Publication statusPublished - Jun 1 2017


  • AGC1 deficiency
  • Brain hypomyelination
  • Mitochondrial aspartate/glutamate carrier
  • N-Acetylaspartate synthesis
  • Neurodegenerative disorders

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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