Established Principles and Emerging Concepts on the Interplay between Mitochondrial Physiology and S-(De)nitrosylation: Implications in Cancer and Neurodegeneration
Effects of NO and nitrosative stress on apoptosis. NO-mediated effect on cell viability and death has been carefully characterized in the last years. For example, Bcl-2 has been reported to be S-nitrosylated and thus modified to be stabilized and not degraded by the Ubiquitin/proteasome system. Cytochrome c has been also indicated to undergo S-nitrosylation in order to bind Apaf1 and procaspase-9 and promote the assembling of the apoptosome. Zymogen procaspase-9, and the executioner pro-caspase3, remain in a quiescent (inactive) form since they are S-nitrosylated in their catalytic cysteine residue in order to avoid unwanted activation of death program. Upon apoptotic stimulus, Trxs are able to denitrosylate caspases, thereby allowing their proteolytic activation and the progression of the apoptotic events downstream it. Recently, it has been also highlighted that the recruitment of the death receptor Fas to lipid rafts of plasma membrane upon binding to its ligand (FasL) is enhanced by S-nitrosylation of Cys304 of its cytoplasmic domain (DD, death domain). In this case S-nitrosylation positively affects the execution of apoptosis that takes place directly via the caspase-8-initiated extrinsic route or can synergize with the mitochondrial pathway through the proteolytic activation of the proapoptotic protein Bid in its truncated form (t-Bid).