Mild Acidosis Protects Neurons during Oxygen-Glucose Deprivation by Reducing Loss of Mitochondrial Respiration
Mild Acidosis Protects Neurons during Oxygen-Glucose Deprivation by Reducing Loss of Mitochondrial Respiration
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轻度酸中毒通过减少线粒体呼吸损失来保护缺氧葡萄糖期间的神经元
DOI：
10.1021/acschemneuro.8b00737
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发表时间：
2019
影响因子：
5
通讯作者：
Chai Zhen
中科院分区：
文献类型：
--
作者：
Zhu Ming-Yue;Zhang Dong-Liang;Zhou Chen;Chai Zhen
脑缺血常伴有脑酸中毒，这种酸中毒可影响缺血性神经元损伤。缺血性神经元损伤是由ATP产生减少引起的，ATP产生减少主要依赖于线粒体氧化磷酸化。缺血常导致线粒体功能障碍，并且已发现酸中毒影响线粒体功能，这表明伴随缺血的酸中毒可能通过靶向线粒体代谢影响神经元。然而，缺血时酸中毒对线粒体能量代谢的影响缺乏深入的研究。在这里，我们发现，轻度酸中毒显着减少神经元死亡可能是通过减缓过程中的ATP剥夺氧-葡萄糖剥夺（OGD），在体外缺血模型。神经元ATP的维持依赖于保护线粒体ATP的产生。线粒体功能的进一步研究表明，轻度酸中毒减轻了OGD诱导的线粒体膜电位的崩溃以及对呼吸功能的损害，至少部分是通过减少对复合物I和II活性的影响。复合物I活性的抑制加重了神经元死亡，这表明轻度酸中毒对维持复合物I活性的贡献促进了OGD期间神经元的存活。我们的研究结果表明，维持线粒体呼吸作为一种新的可能的保护机制，轻度酸中毒缺血期间，对神经元。
Brain ischemia is often accompanied by brain acidosis and this acidosis can affect ischemic neuronal injury. Ischemic neuronal injury is initiated by a decrease in ATP production which mainly relies on mitochondrial oxidative phosphorylation. Ischemia often causes mitochondrial dysfunction, and acidosis has been found to affect mitochondrial function, suggesting that acidosis accompanying ischemia may influence neurons by targeting mitochondrial metabolism. However, the effects of acidosis on mitochondrial energy metabolism during ischemia lacks thorough investigation. Here, we found that mild acidosis significantly reduced neuronal death possibly by slowing the process of ATP deprivation during oxygen-glucose deprivation (OGD), an in vitro ischemic model. The maintaining of neuronal ATP depended on protecting mitochondrial ATP production. Further investigation of mitochondrial function revealed that mild acidosis alleviated OGD-induced collapse of mitochondrial membrane potentials as well as damage to respiratory function, at least in part by reducing impacts on complex I and II activities. Inhibition of complex I activity aggravated neuronal death, which suggests that the contribution of mild acidosis to maintaining complex I activity promoted neuronal survival during OGD. Our findings reveal maintaining mitochondrial respiration as a new possible protective mechanism of mild acidosis during ischemia, on neurons.