Established Principles and Emerging Concepts on the Interplay between Mitochondrial Physiology and S-(De)nitrosylation: Implications in Cancer and Neurodegeneration
Redox network underlying protein thiol-dependent signaling. The key role of sulfur chemistry in cell signaling depends on the capability of specific cysteine residues, named reactive cysteines, of redox sensing proteins (Prot-SH) to undergo reversible oxidations upon deprotonation (formation of a thiolate adduct, Prot-S−). The net negative charge enhances the nucleophilic nature of sulfur and allows the generation of several adducts upon reaction with prooxidant compounds (red-colored). In particular, the encounter of a Prot-S− with H2O2 leads to the hydroxylation of the sulfur moiety with the formation of a still reducible sulfenate derivative (SOH). Further H2O2-mediated oxidations modify sulfur to sulfinic (SO2H) or sulfonic (SO3H) acid species, that are irreversible oxidations, except for the former, that, in some cases (e.g., the sulfinic form of peroxiredoxin), can be reduced back at the expense of ATP by means of sulfiredoxin-mediated catalysis (not shown in the figure). Prot-S− can also undergo S-nitrosylation, thereby generating a Prot-SNO adduct (see Figure 1). Both Prot-SNO and Prot-SOH can exchange with reduced glutathione (GSH), leading to the formation of the more stable S-glutathionylated species (Prot-SSG). Prot-SSG and Prot-SNO are reduced back, respectively, by the glutaredoxin/glutaredoxin reductase (Grx/GrxR) and thioredoxin/thioredoxin reductase (Trx/TrxR) systems, at the expense of NADPH. In addition, Prot-SNO can undergo transnitrosylation reactions with GSH, thereby forming S-nitrosoglutathione (GSNO). This reaction underlies a delicate equilibrium between the redox couples GSH/GSNO and Prot-SH/Prot-SNO that are strictly maintained by GSNO reductase (GSNOR) activity. Indeed, by using GSH-provided reducing equivalents and NADH as cofactor, GSNOR completely reduces GSNO to glutathione disulfide (GSSG) and ammonia (NH3), thereby deeply affecting Prot-SNO concentration. Intracellular GSH availability is also important to detoxify from H2O2 toxicity, as it is the elective cofactor of glutathione peroxidase (GPx). Therefore, GPx and GSNOR indirectly impact (i.e., via GSH oxidation to GSSG) on the total level of the reversibly oxidized proteins (Prot-SOH and Prot-SNO), by directly regulating the concentration of H2O2 and GSNO.