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PNAS 99 (13): 8892-8897

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

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

Belén Beltrán*, Marisol Quintero*, Eugenia García-Zaragozá{dagger}, Enrique O'Connor{ddagger}, Juan V. Esplugues*,{dagger}, and Salvador Moncada§,¶

*Centro Nacional de Investigaciones Cardiovasculares, C/Sinesio Delgado, 6 - Pab.5 28029 Madrid, Spain; {dagger}Departamento de Farmacología, {ddagger}Departamento de Bioquímica, Universidad de Valencia, Blasco Ibanez no. 15, 46010 Valencia, Spain; and §The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom

Contributed by Salvador Moncada

Accepted for publication May 1, 2002.

Abstract: 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 F1Fo-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.

To whom reprint requests should be addressed. E-mail: s.moncada{at}ucl.ac.uk.

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