Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases

Gretchen L. Seim, Steven V. John, Nicholas L. Arp, Zixiang Fang, David J. Pagliarini, Jing Fan

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)265-274
Number of pages10
JournalNature Chemical Biology
Volume19
Issue number3
DOIs
StatePublished - Mar 2023

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