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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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DOI (Published version): 10.1038/s41467-020-14433-7

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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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 1&#x3B1; (Hif1&#x3B1;)-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. 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spelling 2022-11-07T15:27:55.3967146 v2 61685 2022-10-31 Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase ff080296775381560053d5e3a6e81745 0000-0001-7767-4060 Luke Davies Luke Davies true false 2022-10-31 MEDS 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. Journal Article Nature Communications 11 1 Springer Science and Business Media LLC 2041-1723 4 2 2020 2020-02-04 10.1038/s41467-020-14433-7 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 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). 2022-11-07T15:27:55.3967146 2022-10-31T12:01:27.8102441 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Erika M. Palmieri 1 Marieli Gonzalez-Cotto 2 Walter A. Baseler 3 Luke Davies 0000-0001-7767-4060 4 Bart Ghesquière 5 Nunziata Maio 6 Christopher M. Rice 7 Tracey A. Rouault 0000-0003-0062-0245 8 Teresa Cassel 9 Richard M. Higashi 10 Andrew N. Lane 0000-0003-1121-5106 11 Teresa W.-M. Fan 0000-0002-7292-8938 12 David A. Wink 13 Daniel W. McVicar 0000-0002-1112-5111 14 61685__25679__ed206eac29ef460ba10582b10fc147f4.pdf 61685.pdf 2022-11-07T15:26:18.0286988 Output 1976463 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
spellingShingle Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
Luke Davies
title_short Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
title_full Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
title_fullStr Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
title_full_unstemmed Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
title_sort Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
author_id_str_mv ff080296775381560053d5e3a6e81745
author_id_fullname_str_mv ff080296775381560053d5e3a6e81745_***_Luke Davies
author Luke Davies
author2 Erika M. Palmieri
Marieli Gonzalez-Cotto
Walter A. Baseler
Luke 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
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container_title Nature Communications
container_volume 11
container_issue 1
publishDate 2020
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-020-14433-7
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description 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.
published_date 2020-02-04T08:16:16Z
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