Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism.

Autor:	Arp NL; Morgridge Institute for Research, Madison, Wisconsin, USA; Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; University of Wisconsin Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA., Seim GL; Morgridge Institute for Research, Madison, Wisconsin, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA., Votava JA; Morgridge Institute for Research, Madison, Wisconsin, USA., Josephson J; Morgridge Institute for Research, Madison, Wisconsin, USA., Fan J; Morgridge Institute for Research, Madison, Wisconsin, USA; Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; University of Wisconsin Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA. Electronic address: jfan@morgridge.org.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Nov; Vol. 299 (11), pp. 105333. Date of Electronic Publication: 2023 Oct 10.
DOI:	10.1016/j.jbc.2023.105333
Abstrakt:	Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex. Here, we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex-RNS can cause inactivating covalent modifications of the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), decrease of their products (acyl-CoAs), and a lower cellular energy charge. In sum, this work revealed a new mechanism for BCKDC regulation, demonstrated that RNS can generally inhibit all α-ketoacid dehydrogenases, which has broad physiological implications across multiple cell types, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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