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

Research output: Contribution to journalArticle

  • Erika M Palmier
  • 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
  • Daniel W McVicar
Original languageEnglish
Article number698 (2020)
Number of pages17
JournalNature Communications
Volume11
DOIs
DateAccepted/In press - 16 Dec 2019
DatePublished (current) - 4 Feb 2020

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.

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Nature Research at https://doi.org/10.1038/s41467-020-14433-7 . Please refer to any applicable terms of use of the publisher.

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