Shen Yao, Tian Yueyang, Shi Xiaojie, Yang Jianbo, Ouyang Li, Gao Jieqiong, Lu Jianxin
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Cell Biochem Funct. 2014 Aug;32(6):530-7. doi: 10.1002/cbf.3047. Epub 2014 Jul 30.
Astrocytes play a key role in removing the synaptically released glutamate from the extracellular space and maintaining the glutamate below neurotoxic level in the brain. However, high concentration of glutamate leads to toxicity in astrocytes, and the underlying mechanisms are unclear. The purpose of this study was to investigate whether energy metabolism disorder, especially impairment of mitochondrial respiration, is involved in the glutamate-induced gliotoxicity. Exposure to 10-mM glutamate for 48 h stimulated glycolysis and respiration in astrocytes. However, the increased oxygen consumption was used for proton leak and non-mitochondrial respiration, but not for oxidative phosphorylation and ATP generation. When the exposure time extended to 72 h, glycolysis was still activated for ATP generation, but the mitochondrial ATP-linked respiration of astrocytes was reduced. The glutamate-induced astrocyte damage can be mimicked by the non-metabolized substrate d-aspartate but reversed by the non-selective glutamate transporter inhibitor TBOA. In addition, the glutamate toxicity can be partially reversed by vitamin E. These findings demonstrate that changes of bioenergetic profile occur in cultured cortical astrocytes exposed to high concentration of glutamate and highlight the role of mitochondria respiration in glutamate-induced gliotoxicity in cortical astrocytes.
星形胶质细胞在从细胞外空间清除突触释放的谷氨酸并将大脑中的谷氨酸维持在神经毒性水平以下方面发挥着关键作用。然而，高浓度的谷氨酸会导致星形胶质细胞中毒，其潜在机制尚不清楚。本研究的目的是调查能量代谢紊乱，尤其是线粒体呼吸受损，是否与谷氨酸诱导的神经胶质细胞毒性有关。将星形胶质细胞暴露于10 mM谷氨酸48小时会刺激糖酵解和呼吸作用。然而，增加的耗氧量用于质子泄漏和非线粒体呼吸，而不是用于氧化磷酸化和ATP生成。当暴露时间延长至72小时时，糖酵解仍被激活以生成ATP，但星形胶质细胞的线粒体ATP相关呼吸作用降低。非代谢底物D-天冬氨酸可模拟谷氨酸诱导的星形胶质细胞损伤，但非选择性谷氨酸转运体抑制剂TBOA可将其逆转。此外，维生素E可部分逆转谷氨酸毒性。这些发现表明，暴露于高浓度谷氨酸的培养皮质星形胶质细胞会出现生物能量特征的变化，并突出了线粒体呼吸在皮质星形胶质细胞谷氨酸诱导的神经胶质细胞毒性中的作用。
