Established Principles and Emerging Concepts on the Interplay between Mitochondrial Physiology and S-(De)nitrosylation: Implications in Cancer and Neurodegeneration

Mechanisms of S-nitrosylation. Cysteines of low molecular weight (e.g., GSH) and protein sulfhydryls (both termed as RSH) can undergo S-nitrosylation, thus generating S-nitrosothiols (RSNO), by different reactions involving different NO groups and different thiol substrates. RSNO can be formed upon the encountering of with a thiyl radical (), with the latter species deriving from an RSH upon metal-catalyzed oxidation or upon homolytic scission of a disulfide bridge () (on the left). However, as is a rare and chemically unstable species, it is plausible to consider that the majority of cellular RSNO generates from the thiolate form of the cysteine (RS⁻) that can result from sulfur deprotonation even at physiological pH. Either as RS⁻, or directly as RSH, cysteine sulfhydryl can undergo nitrosylation by reacting with NO-derived dinitrogen trioxide (N₂O₃), or directly with nitrosonium ion (NO⁺) generated upon metal-catalyzed oxidation of . The net transfer of NO⁺ from an RSNO to an (transnitrosylation) also occurs inside the cells and represents a further reaction to produce S-nitrosylated adducts (on the right).