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; Daniel W. McVicar

doi:10.1038/s41467-020-14433-7

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, Daniel W. McVicar

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188 Scopus citations

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.

Original language	English
Article number	698
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14433-7
State	Published - Dec 1 2020

Bibliographical note

Funding Information:
We thank Prof. Bernhard Brüne at Goethe-University Frankfurt-Faculty of Medicine for providing Hifα1−/− BMDMs, Jeffrey Subleski (Leukocyte Signaling Section, Cancer & Inflammation Program, National Cancer Institute, Frederick, MD, USA) for its technical assistance and Daniel R. Crooks (Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, USA) for helpful discussions. 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). The content of this publication does not reflect views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization simply endorsement by the U.S.Government.

Publisher Copyright:
© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

ASJC Scopus subject areas

Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)
Physics and Astronomy (all)

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10.1038/s41467-020-14433-7

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Palmieri, E. M., Gonzalez-Cotto, M., Baseler, W. A., Davies, L. C., Ghesquière, B., Maio, N., Rice, C. M., Rouault, T. A., Cassel, T., Higashi, R. M., Lane, A. N., Fan, T. W. M., Wink, D. A., & McVicar, D. W. (2020). Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase. Nature Communications, 11(1), Article 698. https://doi.org/10.1038/s41467-020-14433-7

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title = "Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase",

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.",

author = "Palmieri, {Erika M.} and Marieli Gonzalez-Cotto and Baseler, {Walter A.} and Davies, {Luke C.} and Bart Ghesqui{\`e}re and Nunziata Maio and Rice, {Christopher M.} and Rouault, {Tracey A.} and Teresa Cassel and Higashi, {Richard M.} and Lane, {Andrew N.} and Fan, {Teresa W.M.} and Wink, {David A.} and McVicar, {Daniel W.}",

note = "Funding Information: We thank Prof. Bernhard Br{\"u}ne at Goethe-University Frankfurt-Faculty of Medicine for providing Hifα1−/− BMDMs, Jeffrey Subleski (Leukocyte Signaling Section, Cancer & Inflammation Program, National Cancer Institute, Frederick, MD, USA) for its technical assistance and Daniel R. Crooks (Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, USA) for helpful discussions. 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). The content of this publication does not reflect views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization simply endorsement by the U.S.Government. Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

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Palmieri, EM, Gonzalez-Cotto, M, Baseler, WA, Davies, LC, Ghesquière, B, Maio, N, Rice, CM, Rouault, TA, Cassel, T, Higashi, RM , Lane, AN , Fan, TWM, Wink, DA & McVicar, DW 2020, 'Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase', Nature Communications, vol. 11, no. 1, 698. https://doi.org/10.1038/s41467-020-14433-7

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T1 - Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase

AU - Palmieri, Erika M.

AU - Gonzalez-Cotto, Marieli

AU - Baseler, Walter A.

AU - Davies, Luke C.

AU - Ghesquière, Bart

AU - Maio, Nunziata

AU - Rice, Christopher M.

AU - Rouault, Tracey A.

AU - Cassel, Teresa

AU - Higashi, Richard M.

AU - Lane, Andrew N.

AU - Fan, Teresa W.M.

AU - Wink, David A.

AU - McVicar, Daniel W.

N1 - Funding Information: We thank Prof. Bernhard Brüne at Goethe-University Frankfurt-Faculty of Medicine for providing Hifα1−/− BMDMs, Jeffrey Subleski (Leukocyte Signaling Section, Cancer & Inflammation Program, National Cancer Institute, Frederick, MD, USA) for its technical assistance and Daniel R. Crooks (Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, USA) for helpful discussions. 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). The content of this publication does not reflect views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization simply endorsement by the U.S.Government. Publisher Copyright: © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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

Abstract

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