Costa Renata T, Santos Marcella B, Alberto-Silva Carlos, Carrettiero Daniel C, Ribeiro César A J
Centro de Ciências Naturais E Humanas (CCNH), UFABC - Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo, SP, CEP 09606-045, Brazil.
Cell Mol Neurobiol. 2023 Apr;43(3):1163-1180. doi: 10.1007/s10571-022-01236-1. Epub 2022 Jun 8.
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 (0.1-10 mM) for 24 or 48 h and cell metabolic 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 metabolic viability after 48-h period and increased glucose consumption during the same period of incubation. Regarding the energy homeostasis, MMA significantly reduced respiratory parameters of cells after 48-h exposure, 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 exposure 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. Methylmalonic acid compromises mitochondrial functioning leading to reduced ATP production and reduces glutamate uptake by C6 astroglial cells.
甲基丙二酸血症是一种由L-甲基丙二酰辅酶A变位酶或其辅因子钴胺素活性缺乏引起的有机酸血症，其生化特征是患者组织和体液中甲基丙二酸（MMA）蓄积。该疾病的主要临床表现为神经系统症状，在代谢失代偿期间可观察到的症状有脑病、脑萎缩、昏迷和癫痫发作，这些症状常见于新生儿。本研究旨在调查MMA对具有星形胶质细胞特征的胶质细胞系的毒性作用。将星形胶质细胞C6细胞暴露于MMA（0.1 - 10 mM）中24或48小时，分析细胞代谢活力、葡萄糖消耗、氧消耗率以及谷氨酸摄取和ATP含量。还评估了苯扎贝特可能的预防作用。48小时后，MMA显著降低细胞代谢活力，并在同一孵育期内增加葡萄糖消耗。关于能量稳态，暴露于MMA 48小时后，MMA显著降低细胞的呼吸参数，表明细胞代谢在静息和储备能力状态下受到损害，这可能会影响细胞满足能量需求的能力。暴露于MMA后，谷氨酸摄取和ATP含量也受到损害，这可能受能量代谢损害的影响，进而影响星形胶质细胞的功能。我们的研究结果表明，这些影响可能与该疾病神经功能障碍的病理生理学有关。甲基丙二酸损害线粒体功能，导致ATP生成减少，并降低C6星形胶质细胞对谷氨酸的摄取。
