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

Author

Listed:
  • Erika M. Palmieri

    (National Cancer Institute)

  • Marieli Gonzalez-Cotto

    (National Cancer Institute)

  • Walter A. Baseler

    (National Cancer Institute)

  • Luke C. Davies

    (National Cancer Institute
    Cardiff University, Tenovus Building, Heath Park)

  • Bart Ghesquière

    (Vesalius Research Center, VIB
    Department of Oncology, KU Leuven)

  • Nunziata Maio

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development)

  • Christopher M. Rice

    (National Cancer Institute
    University of Bristol)

  • 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)

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.

Suggested Citation

  • 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 & Andre, 2020. "Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14433-7
    DOI: 10.1038/s41467-020-14433-7
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    Cited by:

    1. Hayden T. Pacl & Krishna C. Chinta & Vineel P. Reddy & Sajid Nadeem & Ritesh R. Sevalkar & Kievershen Nargan & Kapongo Lumamba & Threnesan Naidoo & Joel N. Glasgow & Anupam Agarwal & Adrie J. C. Steyn, 2023. "NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Kelvin Ka-lok Wu & Xiaofan Xu & Manyin Wu & Xiaomu Li & Moinul Hoque & Gloria Hoi Yee Li & Qizhou Lian & Kekao Long & Tongxi Zhou & Hailong Piao & Aimin Xu & Hannah Xiaoyan Hui & Kenneth King-yip Chen, 2024. "MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Juraj Adamik & Paul V. Munson & Deena M. Maurer & Felix J. Hartmann & Sean C. Bendall & Rafael J. Argüello & Lisa H. Butterfield, 2023. "Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Guihong Lu & Xiaojun Wang & Feng Li & Shuang Wang & Jiawei Zhao & Jinyi Wang & Jing Liu & Chengliang Lyu & Peng Ye & Hui Tan & Weiping Li & Guanghui Ma & Wei Wei, 2022. "Engineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Juraj Adamik & Paul V. Munson & Felix J. Hartmann & Alexis J. Combes & Philippe Pierre & Matthew F. Krummel & Sean C. Bendall & Rafael J. Argüello & Lisa H. Butterfield, 2022. "Distinct metabolic states guide maturation of inflammatory and tolerogenic dendritic cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    6. Douglas Adamoski & Larissa M. dos Reis & Ana Carolina Paschoalini Mafra & Felipe Corrêa-da-Silva & Pedro Manoel Mendes de Moraes-Vieira & Ioana Berindan-Neagoe & George A. Calin & Sandra Martha Gomes , 2024. "HuR controls glutaminase RNA metabolism," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    7. Erika M. Palmieri & Ronald Holewinski & Christopher L. McGinity & Ciro L. Pierri & Nunziata Maio & Jonathan M. Weiss & Vincenzo Tragni & Katrina M. Miranda & Tracey A. Rouault & Thorkell Andresson & D, 2023. "Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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