Clementi E, Brown G C, Feelisch M, Moncada S
Wolfson Institute for Biomedical Research, University College London, 140 Tottenham Court Road, London W1P 9LN, United Kingdom.
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7631-6. doi: 10.1073/pnas.95.13.7631.
Both reversible and irreversible inhibition of mitochondrial respiration have been reported following the generation of nitric oxide (NO) by cells. Using J774 cells, we have studied the effect of long-term exposure to NO on different enzymes of the respiratory chain. Our results show that, although NO inhibits complex IV in a way that is always reversible, prolonged exposure to NO results in a gradual and persistent inhibition of complex I that is concomitant with a reduction in the intracellular concentration of reduced glutathione. This inhibition appears to result from S-nitrosylation of critical thiols in the enzyme complex because it can be immediately reversed by exposing the cells to high intensity light or by replenishment of intracellular reduced glutathione. Furthermore, decreasing the concentration of reduced glutathione accelerates the process of persistent inhibition. Our results suggest that, although NO may regulate cell respiration physiologically by its action on complex IV, long-term exposure to NO leads to persistent inhibition of complex I and potentially to cell pathology.
细胞产生一氧化氮（NO）后，已报道出线粒体呼吸的可逆性和不可逆性抑制。利用J774细胞，我们研究了长期暴露于NO对呼吸链不同酶的影响。我们的结果表明，尽管NO以始终可逆的方式抑制复合物IV，但长期暴露于NO会导致复合物I逐渐且持续的抑制，这与细胞内还原型谷胱甘肽浓度的降低相伴。这种抑制似乎是由于酶复合物中关键硫醇的亚硝基化所致，因为通过将细胞暴露于高强度光或补充细胞内还原型谷胱甘肽，它可以立即逆转。此外，降低还原型谷胱甘肽的浓度会加速持续抑制的过程。我们的结果表明，尽管NO可能通过其对复合物IV的作用在生理上调节细胞呼吸，但长期暴露于NO会导致复合物I的持续抑制，并可能导致细胞病变。
