The Roles of NO and H2S in Sperm Biology: Recent Advances and New Perspectives

Abstract

After being historically considered as noxious agents, nitric oxide (NO) and hydrogen sulfide (H₂S) are now listed as gasotransmitters, gaseous molecules that play a key role in a variety of cellular functions. Both NO and H₂S are endogenously produced, enzymatically or non-enzymatically, and interact with each other in a range of cells and tissues. In spite of the great advances achieved in recent decades in other biological systems, knowledge about H₂S function and interactions with NO in sperm biology is in its infancy. Here, we aim to provide an update on the importance of these molecules in the physiology of the male gamete. Special emphasis is given to the most recent advances in the metabolism, mechanisms of action, and effects (both physiological and pathophysiological) of these gasotransmitters. This manuscript also illustrates the physiological implications of NO and H₂S observed in other cell types, which might be important for sperm function. The relevance of these gasotransmitters to several signaling pathways within sperm cells highlights their potential use for the improvement and successful application of assisted reproductive technologies.

Keywords: gasotransmitters; hydrogen sulfide; interaction; metabolism; nitric oxide; spermatozoa.

Figure 1

Common targets of nitric oxide (NO) and hydrogen sulfide (H₂S). The scheme displays the cohesion of H₂S and NO common targets within a cell, focusing on the most sperm-relevant enzymes and proteins. The function of NADPH oxidase and GAPDH directly affects sperm motility, as the latter requires ATP production. The sperm ion channels affect not only sperm function (capacitation, hyperactivation, acrosomal reaction), but also the outcome of the fertilization process. The MAPK complex influences the capacitation and hyperactivation of sperm cells. Colors of arrows indicate the relation with sperm biological process marked by the corresponding color. ERK, extracellular signal-regulated kinase; GAPDH, 3-phosphate dehydrogenase; HNO, nitroxyl; HSNO, thionitrous acid; H₂S, hydrogen sulfide; JNK, C-Jun N-terminal kinase; MAPK, mitogen-activated protein kinases; MEK, MAPK/ERK kinase; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; Raf, rapidly accelerated fibrosarcoma kinase; TRPV, transient receptor potential vanilloid.

Figure 2

A brief insight into the interactions between NO and H₂S that might be relevant for sperm biology. Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; GSNO, S-nitrosoglutathione; HNO, nitroxyl; HSNO, thionitrous acid; H₂S, hydrogen sulfide; iNOS, inducible nitric oxide synthase; NO, nitric oxide; PI3K, phosphoinositide 3-kinase. [32,50,116,117,118,119,123,124,125,126,127,128,129,130].