Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2021

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

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Pascal Reynier

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 acidosisinduced 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.
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Origin : Publication funded by an institution

Dates and versions

inserm-03471979 , version 1 (09-12-2021)

Identifiers

Cite

Clément Adam, Léa Paolini, Naïg Gueguen, Guillaume Mabilleau, Laurence Preisser, et al.. Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming. Nature Communications, 2021, 12 (1), pp.7115. ⟨10.1038/s41467-021-27426-x⟩. ⟨inserm-03471979⟩
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