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

Significance: A burgeoning literature has attributed varied physiological effects to hydrogen sulfide (H₂S), which is a product of eukaryotic sulfur amino acid metabolism. Protein persulfidation represents a major focus of studies elucidating the mechanism underlying H₂S signaling. On the contrary, the capacity of H₂S 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 H₂S with oxidized cysteines to form protein persulfides, its inhibition of complex IV represents a specific mechanism of action. Studies on the dual impact of H₂S 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. H₂S 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 H₂S-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 H₂S, for example, cytoprotection against ischemia-reperfusion injury, through the framework of metabolic reprogramming and ETC remodeling by H₂S. Future Directions: The metabolic ramifications of H₂S in other cellular compartments, for example, the endoplasmic reticulum and the nucleus, as well as the intersections between hypoxia and H₂S signaling are important future directions that merit elucidation. Antioxid. Redox Signal. 38, 57-67.