Endocrine Abstracts (2003) 6 S9


S Moncada

The Wolfson Institute for Biomedical Research, University College London, London, UK.

Nitric oxide (NO) is a ubiquitous gaseous signaling molecule, many of whose physiological roles are mediated through activation of the soluble guanylate cyclase. At physiological concentrations, NO also inhibits the mitochondrial enzyme cytochrome c oxidase (complex IV) in competition with oxygen. We have suggested that the interplay between these two gases allows complex IV to act as an oxygen sensor in cells and have shown that endogenous NO modulates oxygen consumption under basal and stimulated conditions in endothelial cells.

Nitric oxide also plays a variety of pathophysiological roles, some of which may be the consequence of its action at the mitochondrial level. We have found that prolonged exposure to exogenous NO results in persistent inhibition of mitochondrial respiration, which is mainly localized at complex I. This persistent inhibition is preceded by a decrease in the concentration of intracellular glutathione and seems to be a result of oxidative stress due to mitochondrial free radical generation.

We have also been studying the involvement of NO in apoptosis, since both propapoptotic and antiapoptotic actions of NO have been reported. We found that inhibition of mitochondrial respiration by NO results in a relative mitochondrial hyperpolarisation, an occurrence that requires the production of glycolytic ATP. Our studies indicate that this hyperpolarisation is a protective mechanism since neurons, which do not utilize the glycolytic pathway and do not respond to NO by mitochondrial hyperpolarisation, are more susceptible to NO-induced apoptosis than are glycolytically-active astrocytes. Persistent inhibition of respiration by NO over a prolonged time will, however, eventually result in the collapse of membrane potential, ATP depletion and, ultimately, cell death.

We are currently investigating the similarities and differences between hypoxia-induced and NO-induced inhibition of mitochondrial respiration, and are elucidating the specific genes involved in the cellular defence against changes in oxygen availability at the mitochondrial level.

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