biostudies-literatureSeim GLU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNIAID NIH HHSNIGMS NIH HHS265-274https://www.ebi.ac.uk/biostudies/studies/S-EPMC9974485biostudies-literatureUnknown19(3)Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.Nature chemical biologyNitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.PMC9974485F31 AI152280T32 GM140935R35 GM131795R56 AI158958Pagliarini DJFang ZFan JSeim GLJohn SVArp NLfalseNitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.2023-01-01T00:00:00Z2023 Mar2025-04-05T14:21:16.421Z2025-04-05T14:21:16.421ZS-EPMC99744853626635110.1038/s41589-022-01153-w