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

Over the last two decades, hydrogen sulfide (H 2 S) has emerged as an endogenous regulator of a broad range of physiological functions. H 2 S belongs to the class of molecules known as gasotransmitters, which typically include nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H 2 S in various cells and tissues: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST). The present article reviews the regulation of these enzymes as well as the pathways of their enzymatic and nonenzymatic degradation and elimination. The multiple interactions of H 2 S with other labile endogenous molecules (e.g., NO) and reactive oxygen species are also outlined. Next, the various biological targets and signaling pathways are outlined, with special reference to H 2 S or oxidative posttranscriptional modification (persulfidation or sulfhydration) of proteins and the effect of H 2 S on various 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 H 2 S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H 2 S in the regulation of various physiological and cellular functions is reviewed, including the regulation of membrane potential, endo- and exocytosis, regulation of various cell organelles (endoplasmic reticulum, Golgi, mitochondria), regulation of cell movement, cell cycle, cell differentiation, and physiological aspects of regulated cell death. Next, the physiological roles of H 2 S in various cell types and organ systems are overviewed, including the role of H 2 S in red blood cells, immune cells, the central and peripheral nervous systems (with focus on neuronal transmission, learning, and memory formation), and regulation of vascular function (including angiogenesis as well as its specialized roles in the cerebrovascular, renal, and pulmonary vascular beds) and the role of H 2 S in the regulation of special senses, vision, hearing, taste and smell, and pain-sensing. Finally, the roles of H 2 S in the regulation of various organ functions (lung, heart, liver, kidney, urogenital organs, reproductive system, bone and cartilage, skeletal muscle, and endocrine organs) are presented, with a focus on physiology (including physiological aging) but also extending to some common pathophysiological conditions. From these data, a wide array of significant roles of H 2 S in the physiological regulation of all organ functions emerges and the characteristic bell-shaped biphasic effects of H 2 S are highlighted. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified.