In mammalian cells, nitric oxide (NO) synthesis results in the inactivation of several mitochondrial iron-sulfur enzymes involved in ATP synthesis that correlates with the appearance of complexes of the [(NO)2Fe(SR)2] type detectable by electron paramagnetic resonance spectroscopy. More specifically, the activity of two [Fe-S] enzymes was followed during the course of NO synthase expression:mitochondrial aconitase, which catalyzes citrate:isocitrate conversion in the Krebs cycle, and cytoplasmic aconitase, or iron regulatory protein (IRP), a trans-regulator that controls expression at the posttranscriptional level of proteins involved in iron metabolism. In response to physiological stimuli, the synthesis of NO leads to inhibition of enzymatic activities of both mitochondrial and cytoplasmic aconitases, whereas the RNA binding activity of IRP is increased. Coordination of the diffusible gas NO with [Fe-S] clusters is thought to result in impairment of metabolic functions. Here it is proposed that the interplay between NO (or some NO-derived molecule) and [Fe-S] clusters at critical catalytic or allosteric sites is crucial in the response to environmental signals within cells.