Inhibition of mitochondrial respiration by endogenous nitric oxide:: A critical step in Fas signaling

被引:107
作者
Beltrán, B
Quintero, M
García-Zaragozá, E
O'Connor, E
Esplugues, JV
Moncada, S
机构
[1] UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England
[2] Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain
[3] Univ Valencia, Dept Bioquim, Dept Farmacol, Valencia 46010, Spain
关键词
D O I
10.1073/pnas.092259799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We have found that activation of human adult T cell leukemia (Jurkat) cells with anti-Fas Ab leads, in a concentration-dependent manner, to an early burst of production of nitric oxide (NO), which inhibits cell respiration. This results in mitochondrial hyperpolarization, dependent on the hydrolysis of glycolytic ATP by the F1F0-ATPase acting in reverse mode. During this early phase of activation, there is a transient release of superoxide anion. All these processes can be prevented by an inhibitor of NO synthase. Approximately 2 h after stimulation with anti-Fas Ab, a distinct second phase can be detected. This comprises a concentration-dependent collapse in mitochondrial membrane potential, a second wave of free radical production, and activation of caspase-8 leading to apoptosis. This second phase is abolished by an inhibitor of caspase activation. In contrast, inhibition of NO synthesis leads to an enhancement and acceleration of these latter processes, suggesting that the early NO-dependent phase represents a protective mechanism. The significance of the two phases in relation to cell survival and death remains to be studied.
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页码:8892 / 8897
页数:6
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