A Metabolic Paradigm for Hydrogen Sulfide Signaling Electron Transport Chain Plasticity.

A burgeoning literature has attributed varied physiological effects to hydrogen sulfide (HS), which is a product of eukaryotic sulfur amino acid metabolism. Protein persulfidation represents a major focus of studies elucidating the mechanism underlying HS signaling. On the contrary, the capacity of HS to induce reductive stress by targeting the electron transport chain (ETC) and signal by reprogramming redox metabolism has only recently begun to be elucidated. In contrast to the nonspecific reaction of HS with oxidized cysteines to form protein persulfides, its inhibition of complex IV represents a specific mechanism of action. Studies on the dual impact of HS as an ETC substrate and an inhibitor have led to the exciting discovery of ETC plasticity and the use of fumarate as a terminal electron acceptor. HS oxidation combined with complex IV targeting generates mitochondrial reductive stress, which is signaled through the metabolic network, leading to increased aerobic glycolysis, glutamine-dependent reductive carboxylation, and lipogenesis. Insights into HS-induced metabolic reprogramming are ushering in a paradigm shift for understanding the mechanism of its cellular action. It will be critical to reevaluate the physiological effects of HS, for example, cytoprotection against ischemia-reperfusion injury, through the framework of metabolic reprogramming and ETC remodeling by HS. The metabolic ramifications of HS in other cellular compartments, for example, the endoplasmic reticulum and the nucleus, as well as the intersections between hypoxia and HS signaling are important future directions that merit elucidation. 38, 57-67.