Mitochondria Mediate Nitric Oxide‐Induced Cell Death
Mitochondria Mediate Nitric Oxide‐Induced Cell Death
复制标题
线粒体介导一氧化氮诱导的细胞死亡
DOI：
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发表时间：
1999
影响因子：
5.2
通讯作者：
G. Brown
中科院分区：
文献类型：
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作者：
A. Bal;V. Borutaite;G. Brown
在中枢神经系统中，生理浓度的一氧化氮（NO）作为细胞内信使，但在较高浓度时，它可以启动神经毒性级联导致细胞死亡一氧化氮与大脑和其他组织的多种病理过程有关，包括缺血、中风和神经退行性疾病2,3有人提出，一氧化氮的许多生理和病理作用可能是通过抑制线粒体功能，特别是细胞色素氧化酶的抑制来介导的。我们已经证明星形胶质细胞和巨噬细胞被细胞因子和内毒素激活，表达诱导的NO合成酶，产生高达1 μM的NO，并通过NO抑制细胞色素氧化酶抑制自身细胞呼吸和共孵养细胞的呼吸4,5我们已经证明，NO通过抑制突触体呼吸导致突触体释放谷氨酸6，并通过兴奋毒性机制杀死小脑颗粒神经元。在本研究中，我们使用巨噬细胞和pc12细胞作为模型系统来研究线粒体抑制与细胞死亡的关系。我们测试了NO和其他线粒体呼吸链抑制剂是否能诱导凋亡或坏死细胞死亡，以及这是否与线粒体通透性过渡孔的打开和随后的半胱天冬酶的激活有关。
In the central nervous system, nitric oxide (NO) at physiological concentrations acts as an intracellular messenger, but at higher concentrations it can initiate a neurotoxic cascade leading to cell death.1 NO has been implicated in a wide range of pathological processes in the brain and other tissues, including ischemia, stroke, and neurodegenerative diseases.2,3 It has been proposed that a number of the physiological and pathological effects of NO may be mediated by suppression of mitochondrial functions, particularly by inhibition of cytochrome oxidase. We have shown that astrocytes and macrophages activated with cytokines and endotoxin to express the inducible NO synthase produce up to 1 μM NO and inhibit their own cellular respiration and that of coincubated cells via the NO inhibition of cytochrome oxidase.4,5 We have shown that NO causes glutamate release from synaptosomes via inhibition of synaptosomal respiration,6 and kills cerebellar granule neurons by excitotoxic mechanisms. In the present studies we have used macrophages and PC 12 cells as a model system to investigate the relation between mitochondrial inhibition and cell death. We tested whether NO and other inhibitors of mitochondrial respiratory chain can induce apoptotic or necrotic cell death, and whether this is related to opening of the mitochondrial permeability transition pore and subsequent activation of caspases.