Induction of mitochondrial oxidative stress in astrocytes by nitric oxide precedes disruption of energy metabolism
Induction of mitochondrial oxidative stress in astrocytes by nitric oxide precedes disruption of energy metabolism
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DOI：
10.1111/j.1471-4159.2005.03374.x
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发表时间：
2005-10-01
影响因子：
4.7
通讯作者：
Heales, SJR
中科院分区：
文献类型：
--
作者：
Jacobson, J;Duchen, MR;Heales, SJR
线粒体电子传递链（ETC）的抑制最终限制ATP的产生并耗尽细胞ATP。然而，脑线粒体中ETC的单个复合物需要被抑制约50%才能导致ATP合成的显着抑制。此外，ETC是产生细胞内活性氧（ROS）的关键位点，抑制ETC的一种或多种复合物可增加线粒体ROS产生的速率。我们问是否部分抑制ETC，在一定程度上不足以扰乱氧化磷酸化，但可能会诱导ROS的生产。线粒体ROS的慢性增加可能导致ETC的氧化损伤，足以产生ETC功能的长期变化，从而使缺陷复合。我们发现，星形胶质细胞暴露于低浓度的一氧化氮（NO）诱导O-2（.-）这些数据表明，部分ETC抑制NO最初可能会导致氧化应激，而不是ATP耗竭，这可能随后诱导ETC功能的不可逆变化，为一个周期的损害提供了基础。
Inhibition of the mitochondrial electron transport chain (ETC) ultimately limits ATP production and depletes cellular ATP. However, the individual complexes of the ETC in brain mitochondria need to be inhibited by similar to 50% before causing significant depression of ATP synthesis. Moreover, the ETC is the key site for the production of intracellular reactive oxygen species (ROS) and inhibition of one or more of the complexes of the ETC may increase the rate of mitochondrial ROS generation. We asked whether partial inhibition of the ETC, to a degree insufficient to perturb oxidative phosphorylation, might nonetheless induce ROS production. Chronic increase in mitochondrial ROS might then cause oxidative damage to the ETC sufficient to produce prolonged changes in ETC function and so compound the defect. We show that the exposure of astrocytes in culture to low concentrations of nitric oxide (NO) induces an increased rate of O-2(.-) generation that outlasts the presence of NO. No effect was seen on oxygen consumption, lactate or ATP content over the 4-6 h that the cells were exposed to NO. These data suggest that partial ETC inhibition by NO may initially cause oxidative stress rather than ATP depletion, and this may subsequently induce irreversible changes in ETC function providing the basis for a cycle of damage.