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bioRxiv · 10.1101/2021.08.26.457835

Methylmalonic acid impairs cell respiration and glutamate uptake in C6 rat glioma cells

Costa, R. T.·Santos, M. B.·Alberto-Silva, C.·Carrettiero, D. C.·Ribeiro, C. A. J.
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Abstract

Methylmalonic acidemia is an organic acidemia caused by deficient activity of L-methylmalonyl-CoA mutase or its cofactor cyanocobalamin and it is biochemically characterized by an accumulation of methylmalonic acid (MMA) in tissue and body fluids of patients. The main clinical manifestations of this disease are neurological and observable symptoms during metabolic decompensation are encephalopathy, cerebral atrophy, coma, and seizures, which commonly appear in newborns. This study aimed to investigate the toxic effects of MMA in a glial cell line presenting astrocytic features. Astroglial C6 cells were exposed to MMA (0.1-10mM) for 24 or 48 hours and cell viability, glucose consumption and oxygen consumption rate, as well as glutamate uptake and ATP content were analyzed. The possible preventive effects of bezafibrate were also evaluated. MMA significantly reduced cell viability after 48-hour period and increased glucose consumption during the same period of incubation. Regarding the energy homeostasis, MMA significantly reduced respiratory parameters of cells after 48-hour exposition, indicating that cell metabolism is compromised at resting and reserve capacity state, which might influence the cell capacity to meet energetic demands. Glutamate uptake and ATP content were also compromised after exposition to MMA, which can be influenced energy metabolism impairment, affecting the functionality of the astroglial cells. Our findings suggest that these effects could be involved in the pathophysiology of neurological dysfunction of this disease.

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Costa, R. T., Santos, M. B., Alberto-Silva, C., Carrettiero, D. C., Ribeiro, C. A. J.. 2021-08-28. Methylmalonic acid impairs cell respiration and glutamate uptake in C6 rat glioma cells. https://doi.org/10.1101/2021.08.26.457835

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