Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration.
Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration.
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DOI：
10.1016/s0891-5849(02)01327-8
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发表时间：
2003-02
影响因子：
7.4
通讯作者：
V. Stewart;S. Heales
中科院分区：
文献类型：
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作者：
V. Stewart;S. Heales
一氧化氮（NO）的过度产生与几种神经退行性疾病的发病机制有关。线粒体电子传递链的损伤也与这些疾病有关。NO及其有毒代谢物过氧亚硝酸盐（ONOO−）可以抑制线粒体呼吸链，导致能量衰竭并最终导致细胞死亡。脑细胞类型对NO/ONOO−的敏感性似乎存在差异，这可能受到细胞抗氧化状态和在呼吸链明显受损时维持能量需求的能力等因素的影响。虽然细胞因子暴露后NO/ONOO−的形成不会影响星形胶质细胞的存活，但这些分子可能会扩散出去，并对邻近的NO/ONOO−敏感细胞（如神经元）造成线粒体损伤。有证据表明，NO/ONOO−导致神经元谷氨酸的释放，导致谷氨酸诱导的神经元NO合酶的激活和进一步破坏物种的产生。虽然神经元似乎能够从短期暴露于NO/ONOO−中恢复，但延长暴露时间会导致呼吸链的持续损伤和细胞死亡。这些发现对急性感染与慢性神经炎性疾病状态具有重要意义。NO/ONOO−介导的线粒体损伤在神经退行性疾病的证据进行审查和潜在的治疗策略进行了讨论。
Excessive generation of nitric oxide (NO) has been implicated in the pathogenesis of several neurodegenerative disorders. Damage to the mitochondrial electron transport chain has also been implicated in these disorders. NO and its toxic metabolite peroxynitrite (ONOO−) can inhibit the mitochondrial respiratory chain, leading to energy failure and ultimately cell death. There appears to be a differential susceptibility of brain cell types to NO/ONOO−, which may be influenced by factors including cellular antioxidant status and the ability to maintain energy requirements in the face of marked respiratory chain damage. Although formation of NO/ONOO−following cytokine exposure does not affect astrocyte survival, these molecules may diffuse out and cause mitochondrial damage to neighboring NO/ONOO−-sensitive cells such as neurons. Evidence suggests that NO/ONOO−causes release of neuronal glutamate, leading to glutamate-induced activation of neuronal NO synthase and generation of further damaging species. While neurons appear able to recover from short-term exposure to NO/ONOO−, extending the period of exposure results in persistent damage to the respiratory chain and cell death ensues. These findings have important implications for acute infection vs. chronic neuroinflammatory disease states. The evidence for NO/ONOO−-mediated mitochondrial damage in neurodegenerative disorders is reviewed and potential therapeutic strategies are discussed.