Hydrogen sulfide stimulates lipid biogenesis from glutamine that is dependent on the mitochondrial NAD(P)H pool

Mammalian cells synthesize H 2 S from sulfur-containing amino acids and are also exposed to exogenous sources of this signaling molecule, notably from gut microbes. As an inhibitor of complex IV in the electron transport chain, H 2 S can have a profound impact on metabolism, suggesting the hypothesis that metabolic reprogramming is a primary mechanism by which H 2 S signals. In this study, we report that H 2 S increases lipogenesis in many cell types, using carbon derived from glutamine rather than from glucose. H 2 S-stimulated lipid synthesis is sensitive to the mitochondrial NAD(P)H pools and is enabled by reductive carboxylation of α-ketoglutarate. Lipidomics analysis revealed that H 2 S elicits time-dependent changes across several lipid classes, e.g. , upregulating triglycerides while downregulating phosphatidylcholine. Direct analysis of triglyceride concentration revealed that H 2 S induces a net increase in the size of this lipid pool. These results provide a mechanistic framework for understanding the effects of H 2 S on increasing lipid droplets in adipocytes and population studies that have pointed to a positive correlation between cysteine (a substrate for H 2 S synthesis) and fat mass.