nder physiological conditions, nitric oxide (NO)-dependent signaling pathways function through different mechanisms involving the interaction with metal centers and the modification of proteins through amino acid residues. For example, the wellknown interaction of soluble guanylate cyclase with NO involves reversible binding to the ferrous heme of the enzyme and increased synthesis of cGMP through this allosteric regulation. 1 By analogy with multiple examples of the reversible and controlled activation of receptors by second messengers, this interaction of NO can be classified as a "classical" receptor-mediated signaling pathway. 2 Recently, a similar heme nitrosylation reaction has also been identified in the mitochondrion with the terminal member of the electron transport chain cytochrome c oxidase. [3][4][5] Binding of NO to this enzyme results in the reversible inhibition of mitochondrial respiration, the increased reduction of distal members of the respiratory chain and, as a consequence, increased formation of superoxide which is then converted by the enzyme MnSOD to hydrogen peroxide. 6,7 It is these conditions which result in the posttranslational modification of proteins including S-nitrosation and tyrosine nitration. The current debate in the area of redox biology is centered on determining to what extent the posttranslational modifications contribute to cell signaling or the mechanisms of disease.
In this respect, mitochondria are particularly interesting since they are both a source and target of reactive oxygen and nitrogen species (ROS/RNS). Initially, ROS formation from the mitochondrion was regarded as symptomatic of bioenergetic dysfunction and therefore deleterious. This perspective is now changing with the recognition that diffusion of hydrogen peroxide from the organelle results in the activation of specific redox cell signaling pathways. 7-10 While many details of these mech-