Abstract
Significance: A burgeoning literature has attributed varied physiological effects to hydrogen sulfide (H(2)S), which is a product of eukaryotic sulfur amino acid metabolism. Protein persulfidation represents a major focus of studies elucidating the mechanism underlying H(2)S signaling. On the contrary, the capacity of H(2)S to induce reductive stress by targeting the electron transport chain (ETC) and signal by reprogramming redox metabolism has only recently begun to be elucidated. Recent Advances: In contrast to the nonspecific reaction of H(2)S with oxidized cysteines to form protein persulfides, its inhibition of complex IV represents a specific mechanism of action. Studies on the dual impact of H(2)S 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. H(2)S 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. Critical Issues: Insights into H(2)S-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 H(2)S, for example, cytoprotection against ischemia-reperfusion injury, through the framework of metabolic reprogramming and ETC remodeling by H(2)S. Future Directions: The metabolic ramifications of H(2)S in other cellular compartments, for example, the endoplasmic reticulum and the nucleus, as well as the intersections between hypoxia and H(2)S signaling are important future directions that merit elucidation. Antioxid. Redox Signal. 38, 57-67.