Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Glia. 2019 Apr;67(4):759-774. doi: 10.1002/glia.23574. Epub 2019 Jan 9.
Astrocytes respond to energetic demands by upregulating glycolysis, lactate production, and respiration. This study addresses the role of respiration and calcium regulation of respiration as part of the astrocyte response to the workloads caused by extracellular ATP and glutamate. Extracellular ATP (100 μM to 1 mM) causes a Ca -dependent workload and fall of the cytosolic ATP/ADP ratio which acutely increases astrocytes respiration. Part of this increase is related to a Ca -dependent upregulation of cytosolic pyruvate production. Conversely, glutamate (200 μM) causes a Na , but not Ca , dependent workload even though glutamate-induced Ca signals readily reach mitochondria. The glutamate workload triggers a rapid fall in the cytosolic ATP/ADP ratio and stimulation of respiration. These effects are mimicked by D-aspartate a nonmetabolized agonist of the glutamate transporter, but not by a metabotropic glutamate receptor agonist, indicating a major role of Na -dependent workload in stimulated respiration. Glutamate-induced increase in respiration is linked to a rapid increase in glycolytic pyruvate production, suggesting that both glutamate and extracellular ATP cause an increase in astrocyte respiration fueled by workload-induced increase in pyruvate production. However, glutamate-induced pyruvate production is partly resistant to glycolysis blockers (iodoacetate), indicating that oxidative consumption of glutamate also contributes to stimulated respiration. As stimulation of respiration by ATP and glutamate are similar and pyruvate production smaller in the first case, the results suggest that the response to extracellular ATP is a Ca -dependent upregulation of respiration added to glycolysis upregulation. The global contribution of astrocyte respiratory responses to brain oxygen consumption is an open question.
星形胶质细胞通过上调糖酵解、乳酸生成和呼吸来响应能量需求。本研究探讨了呼吸作用以及钙对呼吸作用的调节在星形胶质细胞响应细胞外 ATP 和谷氨酸引起的工作量中的作用。细胞外 ATP（100μM 至 1mM）会引起 Ca 依赖性工作量和细胞质 ATP/ADP 比的下降，从而急性增加星形胶质细胞的呼吸作用。这种增加的一部分与 Ca 依赖性细胞质丙酮酸生成的上调有关。相反，谷氨酸（200μM）引起 Na 依赖性工作量，但不引起 Ca 依赖性工作量，尽管谷氨酸诱导的 Ca 信号很容易到达线粒体。谷氨酸工作量会引发细胞质 ATP/ADP 比的迅速下降和呼吸作用的刺激。这种效应被 D-天冬氨酸模拟，D-天冬氨酸是谷氨酸转运体的非代谢激动剂，但不是代谢型谷氨酸受体激动剂，表明 Na 依赖性工作量在刺激呼吸中的主要作用。谷氨酸诱导的呼吸增加与糖酵解丙酮酸生成的迅速增加有关，这表明谷氨酸和细胞外 ATP 都会引起星形胶质细胞呼吸的增加，这是由工作量引起的丙酮酸生成增加所驱动的。然而，谷氨酸诱导的丙酮酸生成对糖酵解抑制剂（碘乙酸盐）有一定的抗性，表明谷氨酸的氧化消耗也有助于刺激呼吸。由于 ATP 和谷氨酸对呼吸的刺激作用相似，而前者的丙酮酸生成较小，因此结果表明，对细胞外 ATP 的反应是除了糖酵解上调之外，还增加了对呼吸作用的 Ca 依赖性上调。星形胶质细胞呼吸反应对大脑耗氧量的总体贡献是一个悬而未决的问题。
