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

The mitochondrial aspartate-glutamate carrier isoform 1 (AGCI) 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, AGCI 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 AGCI gene cause AGCI deficiency, an infantile encephalopathy with delayed myelination and reduced brain N-acetylaspartate (NM) levels, the precursor of myelin synthesis in the CNS. Here, we show that undifferentiated Neuro2A cells with down-regulated AGCI display a significant proliferation deficit associated with reduced mitochondria( respiration, and are unable to synthesize NAA properly. In the presence of high glutamine oxidation, cells with reduced AGO restore cell proliferation, although oxidative stress increases and NAA synthesis deficit persists. Our data suggest that the cellular energetic deficit due to AGCI 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 AGCI deficiency patients could be attributable, at least in part, to neuronal loss combined with lack of NM synthesis occurring during the nervous system development. (C) 2017 Elsevier B.V. All rights reserved.