Inhibition of autophagy and glycolysis by nitric oxide during hypoxia-reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons.
Inhibition of autophagy and glycolysis by nitric oxide during hypoxia-reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons.
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DOI：
10.1016/j.freeradbiomed.2013.09.006
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发表时间：
2013-12
影响因子：
7.4
通讯作者：
Zhang, Jianhua
中科院分区：
文献类型：
--
作者：
Benavides, Gloria A.;Liang, Qiuli;Dodson, Matthew;Darley-Usmar, Victor;Zhang, Jianhua
已知过量的一氧化氮（NO）产生会损害线粒体蛋白和自噬修复途径，因此可能导致神经毒性。因此，我们假设，保护蛋白质损伤的活性氧和氮物种（ROS/RNS）在低氧条件下的神经元中的自噬途径将受到NO的损害，并增强生物能量功能障碍。大鼠原代皮层神经元维持相同的基础细胞呼吸在缺氧常氧，而NO暴露的细胞表现出逐渐减少的线粒体呼吸在缺氧。在复氧后，NO处理的细胞中的呼吸没有恢复到缺氧前的水平。在NO存在下的缺氧-复氧与自噬的抑制有关，并且自噬抑制剂3-甲基腺嘌呤加剧了复氧期间的恢复能力。在常氧条件下，缺氧的影响可以通过抑制糖酵解通量来重现。在常氧和缺氧条件下，NO暴露诱导立即刺激糖酵解，但延长NO暴露，与不可逆的抑制线粒体呼吸缺氧，抑制糖酵解。重要的是，我们发现，只有当葡萄糖不存在于培养基或糖酵解被2-脱氧-D-葡萄糖抑制时，NO才能抑制在常氧条件下的基础呼吸，揭示了一种新的NO依赖性机制，用于抑制由糖酵解调节的线粒体呼吸。总之，这些数据表明线粒体呼吸，糖酵解和自噬之间的氧依赖性相互作用，以保护暴露于NO的神经元细胞。重要的是，它们表明线粒体功能障碍与暴露于NO诱导的糖酵解通量失败密切相关。此外，这些研究为理解自噬和NO如何在神经炎症中发挥相互作用提供了新的见解-诱导的细胞损伤，这与我们对其中产生过量NO的病理学神经变性疾病的理解有关。
Excessive nitric oxide (NO) production is known to damage mitochondrial proteins and the autophagy repair pathway and so can potentially contribute to neurotoxicity. Accordingly, we hypothesized that protection against protein damage from reactive oxygen and nitrogen species (ROS/RNS) under conditions of low oxygen by the autophagy pathway in neurons would be impaired by NO and enhance bioenergetic dysfunction. Rat primary cortical neurons maintained the same basal cellular respiration in hypoxia as normoxia, whereas NO exposed cells exhibited a gradual decrease in mitochondrial respiration in hypoxia. Upon reoxygenation, the respiration in NO treated cells did not recover to pre-hypoxic levels. Hypoxia-reoxygenation in the presence of NO was associated with inhibition of autophagy and the inability to recovery during reoxygenation was exacerbated by the inhibitor of autophagy, 3-methyladenine. The effects of hypoxia could be recapitulated by inhibiting glycolytic flux under normoxic conditions. Under both normoxic and hypoxic conditions NO exposure induced immediate stimulation of glycolysis but prolonged NO exposure, associated with irreversible inhibition of mitochondrial respiration in hypoxia, inhibited glycolysis. Importantly, we found that NO inhibited basal respiration under normoxic conditions only when glucose was absent from the media or glycolysis was inhibited by 2-deoxy-D-glucose, revealing a novel NO-dependent mechanism for the inhibition of mitochondrial respiration which is modulated by glycolysis. Taken together these data suggest an oxygen-dependent interaction between mitochondrial respiration, glycolysis and autophagy in protecting neuronal cells exposed to NO. Importantly, they indicate that mitochondrial dysfunction is intimately linked to a failure of glycolytic flux induced by exposure to NO. In addition, these studies provide new insights into understanding how autophagy and NO may play an interactive role in neuroinflammation-induced cellular damage which is pertinent to our understanding of the pathology neurodegenerative diseases in which excessive NO is generated.
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影响因子：
7.4
作者：
Gerencser, Akos A.;Neilson, Andy;Choi, Sung W.;Edman, Ursula;Yadava, Nagendra;Oh, Richard J.;Ferrick, David A.;Nicholls, David G.;Brand, Martin D.
通讯作者：
Brand, Martin D.
影响因子：
7.4
作者：
Dodson, Matthew;Darley-Usmar, Victor;Zhang, Jianhua
通讯作者：
Zhang, Jianhua
影响因子：
7.4
作者：
Dranka, Brian P.;Hill, Bradford G.;Darley-Usmar, Victor M.
通讯作者：
Darley-Usmar, Victor M.
DOI：
10.1042/bj20111451
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Lee J;Giordano S;Zhang J
通讯作者：
Zhang J
影响因子：
3.7
作者：
Hill BG;Benavides GA;Lancaster JR Jr;Ballinger S;Dell'Italia L;Jianhua Z;Darley-Usmar VM
通讯作者：
Darley-Usmar VM