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

Erika M. Palmieri, Marieli Gonzalez-Cotto, Walter A. Baseler, Luke C. Davies, Bart Ghesquière, Nunziata Maio, Christopher M. Rice, Tracey A. Rouault, Teresa Cassel, Richard M. Higashi, Andrew N. Lane, Teresa W.-M. Fan, David A. Wink and Daniel W. McVicar ()
Additional contact information
Erika M. Palmieri: National Cancer Institute
Marieli Gonzalez-Cotto: National Cancer Institute
Walter A. Baseler: National Cancer Institute
Luke C. Davies: National Cancer Institute
Bart Ghesquière: Vesalius Research Center, VIB
Nunziata Maio: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Christopher M. Rice: National Cancer Institute
Tracey A. Rouault: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Teresa Cassel: University of Kentucky
Richard M. Higashi: University of Kentucky
Andrew N. Lane: University of Kentucky
Teresa W.-M. Fan: University of Kentucky
David A. Wink: National Cancer Institute
Daniel W. McVicar: National Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14433-7

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