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 - Funding Information:
We thank M. Marletta at University of California, Berkeley for helpful discussions. This work was supported by National Institutes of Health (NIH) award R56 AI158958 (J.F.), National Reseach Service Award Individual Predoctoral Fellowship F31AI152280 (G.L.S.), also in part by funds from the BJC Investigator Program (D.J.P.) and NIH award R35 GM131795 (D.J.P.).
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 -