Skip to Main content Skip to Navigation
Journal articles

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

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.
Document type :
Journal articles
Complete list of metadata

https://www.hal.inserm.fr/inserm-03471979
Contributor : Elizabeth Bernardo Connect in order to contact the contributor
Submitted on : Thursday, December 9, 2021 - 9:24:48 AM
Last modification on : Wednesday, April 27, 2022 - 4:44:53 AM

File

Adam_et_al-2021-Nature_Communi...
Publication funded by an institution

Identifiers

Citation

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, Nature Publishing Group, 2021, 12 (1), pp.7115. ⟨10.1038/s41467-021-27426-x⟩. ⟨inserm-03471979⟩

Share

Metrics

Record views

26

Files downloads

32