Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase

Palmieri, Erika M., Gonzalez-Cotto, Marieli, Baseler, Walter A., Davies, Luke C., Ghesquière, Bart, Maio, Nunziata, Rice, Christopher M., Rouault, Tracey A., Cassel, Teresa, Higashi, Richard M., Lane, Andrew N., Fan, Teresa W.-M., Wink, David A. and McVicar, Daniel W. 2020. Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase. Nature Communications 11 (1) , 698. 10.1038/s41467-020-14433-7

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Abstract

Profound metabolic changes are characteristic of macrophages during classical activation and have been implicated in this phenotype. Here we demonstrate that nitric oxide (NO) produced by murine macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization. 13C tracing and mitochondrial respiration experiments map NO-mediated suppression of metabolism to mitochondrial aconitase (ACO2). Moreover, we find that inflammatory macrophages reroute pyruvate away from pyruvate dehydrogenase (PDH) in an NO-dependent and hypoxia-inducible factor 1α (Hif1α)-independent manner, thereby promoting glutamine-based anaplerosis. Ultimately, NO accumulation leads to suppression and loss of mitochondrial electron transport chain (ETC) complexes. Our data reveal that macrophages metabolic rewiring, in vitro and in vivo, is dependent on NO targeting specific pathways, resulting in reduced production of inflammatory mediators. Our findings require modification to current models of macrophage biology and demonstrate that reprogramming of metabolism should be considered a result rather than a mediator of inflammatory polarization.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	11 February 2020
Date of Acceptance:	16 December 2019
Last Modified:	02 May 2023 14:17
URI:	https://orca.cardiff.ac.uk/id/eprint/129523

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