NO Survival Signal

Science's STKE  02 Jul 2002:
Vol. 2002, Issue 139, pp. tw228-TW228
DOI: 10.1126/stke.2002.139.tw228

In certain situations, cells experience conflicting signals such as proapoptotic and prosurvival signals and it is the balance of two that seems to determine the cell's response. Beltrán et al. describe an example of such conflict in cells stimulated through the receptor Fas. Activation of Fas in Jurkat (human adult T cell leukemia) cells causes cells to undergo apoptosis, but the authors found that the early phases of Fas signaling actually produced a protective effect on the mitochondria. In the first hour, treatment of cells with antibody to Fas caused increased production of intracellular nitric oxide (NO). NO inhibits cytochrome oxidase (complex IV) and thus caused decreased respiration and hyperpolarization of the mitochondria. Later, after about 2 hours, a second phase occurred in which the mitochondrial membrane potential was depolarized, caspases were activated, and the cells died. The second deadly phase was accelerated if the early generation of NO was blocked with an inhibitor of NO synthase. Thus, the authors propose that the early phase response is part of a protective mechanism that is ultimately overwhelmed by the later events that cause apoptosis.

B. Beltrán, M. Quintero, E. García-Zaragozá, E. O'Connor, J. V. Esplugues, S. Moncada, Inhibition of mitochondrial respiration by endogenous nitric oxide: A critical step in Fas signaling. Proc. Natl. Acad. Sci. U.S.A. 99, 8892-8897 (2002). [Abstract] [Full Text]