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Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming

Author

Listed:
  • Clément Adam

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT)

  • Léa Paolini

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT)

  • Naïg Gueguen

    (Univ Angers, CHU d’Angers, INSERM, CNRS, MitoVasc, SFR ICAT
    CHU d’Angers)

  • Guillaume Mabilleau

    (Université d’Angers
    CHU d’Angers)

  • Laurence Preisser

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT)

  • Simon Blanchard

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT
    Laboratoire d’Immunologie et Allergologie, CHU d’Angers)

  • Pascale Pignon

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT)

  • Florence Manero

    (Univ Angers, SFR ICAT, SCIAM)

  • Morgane Mao

    (Univ Angers, CHU d’Angers, INSERM, CNRS, MitoVasc, SFR ICAT)

  • Alain Morel

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT
    Institut de Cancérologie de l’Ouest)

  • Pascal Reynier

    (CHU d’Angers)

  • Céline Beauvillain

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT
    Laboratoire d’Immunologie et Allergologie, CHU d’Angers)

  • Yves Delneste

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT
    Laboratoire d’Immunologie et Allergologie, CHU d’Angers)

  • Vincent Procaccio

    (Univ Angers, CHU d’Angers, INSERM, CNRS, MitoVasc, SFR ICAT
    CHU d’Angers)

  • Pascale Jeannin

    (Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT
    Laboratoire d’Immunologie et Allergologie, CHU d’Angers)

Abstract

Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.

Suggested Citation

  • Clément Adam & Léa Paolini & Naïg Gueguen & Guillaume Mabilleau & Laurence Preisser & Simon Blanchard & Pascale Pignon & Florence Manero & Morgane Mao & Alain Morel & Pascal Reynier & Céline Beauvilla, 2021. "Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27426-x
    DOI: 10.1038/s41467-021-27426-x
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    References listed on IDEAS

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