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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 Davies Orcid Logo, Bart Ghesquière, Nunziata Maio, Christopher M. Rice, Tracey A. Rouault Orcid Logo, Teresa Cassel, Richard M. Higashi, Andrew N. Lane Orcid Logo, Teresa W.-M. Fan Orcid Logo, David A. Wink, Daniel W. McVicar Orcid Logo

Nature Communications, Volume: 11, Issue: 1

Swansea University Author: Luke Davies Orcid Logo

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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 polarizatio...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2020
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URI: https://cronfa.swan.ac.uk/Record/cronfa61685
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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.
College: Faculty of Medicine, Health and Life Sciences
Funders: This research was supported, in part, by the intramural Research Program of the NIH, National Cancer Institute USA, 1U24DK097215-01A1 (to RMH, TWMF, and ANL), and Redox Metabolism Shared Resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). L.C.D. is funded in part by and the Henry Wellcome Trust, UK (WT103973MA).
Issue: 1