Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs

Abstract

H2S belongs to the class of molecules known as gasotransmitters, which also includes nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine g-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current article reviews the regulation of these enzymes as well as the pathways of their enzymatic and non-enzymatic degradation and elimination. The multiple interactions of H2S with other labile endogenous molecules (e.g. NO) and reactive oxygen species are also outlined. The various biological targets and signaling pathways are discussed, with special reference to H2S and oxidative posttranscriptional modification of proteins, the effect of H2S on channels and intracellular second messenger pathways, the regulation of gene transcription and translation and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study H2S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H2S in the regulation of various physiological and cellular functions is reviewed. The physiological role of H2S in various cell types and organ systems are overviewed. Finally, the role of H2S in the regulation of various organ functions is discussed as well as the characteristic bell-shaped biphasic effects of H2S. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

“…Taken together, in control cells H 2 S does not appear to play a large role in modulating mitochondrial function and proliferation, while in DS cells, the elevated H 2 S levels exerts inhibitory effects on mitochondrial function and cell proliferation. Indeed, H 2 S has a well-documented ability to inhibit mitochondrial Complex IV, leading to the suppression of cellular bioenergetics and cell viability; an action which has been well characterized by earlier environmental toxicological and biochemical studies [ 3 , 4 , 17 , 18 ].

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“…However, the proteomic analysis did not reveal very significant differences in the expression of enzymes involved in the regulation of central carbon metabolism, yielding the overall conclusion is that the changes that we observe in terms of bioenergetics and fluxomics are not principally driven by changes in rate limiting enzyme levels, but, rather, by functional biochemical effects, which may be driven by mechanisms that regulate the catalytic activity, rather than the expression level of these proteins. Among many mediators, H 2 S can induce such effects, for instance through persulfidation of protein cysteines or through its actions on metal-containing active centers [ 4 ]. For instance, in cancer cells, H 2 S has been shown to drive SQR-dependent respiration causing a reversal of the TCA cycle, glutamine deprivation, increased glycolysis and lipogenesis – effects that are not ultimately linked to altered expression of SQR protein [ 42 ].…”

“… Finally, we should briefly consider the limitations of the pharmacological agent, AOAA. This molecule has been widely used in the literature to inhibit the catalytic activity of CBS in order to study various processes ranging from cancer metabolism to the neurotransmission, vascular function, hypoxia sensing and others, principally due to the fact that available pharmacological options to inhibit CBS are very limited [ 3 , 4 , 34 ]. However, the effects of AOAA, as far as the modulation of H 2 S homeostasis is concerned, go beyond CBS; this compound, as a broad inhibitor of PLP-dependent enzymes, as well as an inhibitor of another H 2 S-generating enzyme, CSE [ 74 , 75 ].…”

“…One of the genes that chromosome 21 codes for is the gene for cystathionine β-synthase (CBS, EC 4.2.1.22), a major enzyme in the transsulfuration pathway and one of the principal enzymes responsible for the synthesis of the gaseous transmitter hydrogen sulfide (H 2 S). H 2 S is now recognized as a significant mammalian biological regulator in health and disease [ 3 , 4 ]. As a result of the “gene dosage effect”, CBS is overexpressed in DS, and this has been long suspected to be a ‘master switch’ in the pathophysiology of DS [ 5 , 6 ].…”

The Potential Implications of Hydrogen Sulfide in Aging and Age-Related Diseases through the Lens of Mitohormesis

“…Interestingly, H 2 S has also been found to alleviate oxidative stress and maintain redox homeostasis through its ability to upregulate the cellular antioxidant mechanisms in an Nrf2-dependent manner [ 54 ]. Increasing evidence suggests that modifying thiol groups of cysteine residues in target proteins via S-sulfhydration or persulfidation is an important post-translational modification by H 2 S that is responsible for the biological functions of this gaseous signaling molecule [ 55 , 56 ]. Some animal studies have demonstrated that H 2 S donors that release H 2 S can S-sulfhydrate Keap1 at cysteine-151, leading to Nrf2 dissociation from Keap1 and promoting Nrf2 nuclear translocation, ultimately inducing the expression of downstream protective genes [ 57 , 58 , 59 ].…”