Persulfide-Dependent Regulation of Electrophilic Redox Signaling in Neural Cells

Redox homeostasis is precisely modulated by intricate systems that regulate production, elimination, and metabolism of electrophilic substances (electrophiles) in the nervous system. Since the first report of the endogenous production of reactive persulfide species in cells, such as cysteine persulfides (CysSSH), these reactive species have been a topic of extreme interest in the field of redox biology; persulfides/polysulfides possess unique chemical properties and are involved in multiple cellular functions. Electrophilic signaling is mainly regulated by endogenous electrophiles that are generated from reactive oxygen species, nitric oxide, and their derivatives during stress responses, as well as by exogenous electrophiles, including compounds in foods and environmental pollutants, such as methylmercury (MeHg). Among diverse electrophiles that are endogenously generated, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) possesses unique redox properties, of which the biosynthetic pathway, signaling mechanism, and metabolism in cells have been elucidated. Persulfides, such as CysSSH, that are endogenously produced are critically involved in 8-nitro-cGMP metabolism. Exposure of neurons to the exogenous neurotoxicant, MeHg, causes severe neurodegeneration via disruption of persulfide-dependent 8-nitro-cGMP metabolism. Accumulating evidence indicates that persulfides are involved in various cellular functions under physiological and pathological conditions. These new aspects of redox biology related to persulfides may be frontiers of cell research, medical and clinical investigations of neurodegenerative diseases, as well as other fields. 8-Nitro-cGMP-mediated signaling and its persulfide-dependent metabolism in cells could, therefore, be potential targets for drug development, which may lead to the discovery of new therapeutic agents for many diseases, including neurodegenerative diseases.