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

Clément Adam, Léa Paolini, Naïg Gueguen, Guillaume Mabilleau, Laurence Preisser, Simon Blanchard, Pascale Pignon, Florence Manero, Morgane Mao, Alain Morel, Pascal Reynier, Céline Beauvillain, Yves Delneste, Vincent Procaccio and Pascale Jeannin ()
Additional contact information
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
Guillaume Mabilleau: Université 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
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
Pascal Reynier: CHU d’Angers
Céline Beauvillain: Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT
Yves Delneste: Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT
Vincent Procaccio: Univ Angers, CHU d’Angers, INSERM, CNRS, MitoVasc, SFR ICAT
Pascale Jeannin: Univ Angers, Université de Nantes, INSERM, CRCINA, LabEx IGO, SFR ICAT

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27426-x

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