Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells

Abstract

Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.

Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress

“…This indicates that RSS are involved in the repression of electrophile-mediated toxicity by the formation of inactive metabolites of electrophiles. Consistent with this notion, the toxicity of MeHg, Cd and 1,4-NQ was effectively blocked by treatment with the model polysulfide Na 2 S 4 [75,77,80].…”

Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides

“…RSS• are considerably less reactive compared to their thiyl radical counterparts, and hence, are probably less toxic if produced in cells. Persulfide/polysulfide species can also efficiently react with various electrophiles [ 5 , 48 ]. 8-Nitro-cGMP is an endogenously occurring weak electrophile and acts as a second messenger in redox signaling [ 49 , 50 ].…”

Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells

“…ROS are produced during inflammation and infection and induce oxidative stress. CysSSH effectively reacted with 8-nitro-cGMP to form 8-SH-cGMP and thereby nullified the electrophilic signalling activity of 8-nitro-cGMP (Nishida et al, 2012;Ida et al, 2014;Ihara et al, 2017). Some electrophiles that depend on ROS and RNS for formation, however, are endogenous signalling molecules and mediate redox signalling (Forman et al, 2004;Sies, 2014).…”

“…We have studied the signalling mechanisms and physiological roles of 8-nitro-cGMP and found that the signalling by this compound is regulated by CysSSH in cells. CysSSH effectively reacted with 8-nitro-cGMP to form 8-SH-cGMP and thereby nullified the electrophilic signalling activity of 8-nitro-cGMP (Nishida et al, 2012;Ida et al, 2014;Ihara et al, 2017). We developed a quantitative analytical system for the persulfide/polysulfide species of cysteine and related compounds that involved LC-MS-MS and found that different amounts of various persulfide/polysulfide species were produced in mammalian cells (Ida et al, 2014).…”