TY - JOUR
T1 - Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases
AU - Seim, Gretchen L.
AU - John, Steven V.
AU - Arp, Nicholas L.
AU - Fang, Zixiang
AU - Pagliarini, David J.
AU - Fan, Jing
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2023/3
Y1 - 2023/3
N2 - 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.].
AB - 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.].
UR - http://www.scopus.com/inward/record.url?scp=85140240660&partnerID=8YFLogxK
U2 - 10.1038/s41589-022-01153-w
DO - 10.1038/s41589-022-01153-w
M3 - Article
C2 - 36266351
AN - SCOPUS:85140240660
SN - 1552-4450
VL - 19
SP - 265
EP - 274
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 3
ER -