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

• Published in: Nature communications 2021-12, Vol.12 (1), p.7115-7115, Article 7115
• Main Authors: Adam, Clément, Paolini, Léa, Gueguen, Naïg, Mabilleau, Guillaume, Preisser, Laurence, Blanchard, Simon, Pignon, Pascale, Manero, Florence, Le Mao, Morgane, Morel, Alain, Reynier, Pascal, Beauvillain, Céline, Delneste, Yves, Procaccio, Vincent, Jeannin, Pascale
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/21; 13/31; 14; 14/28; 38/77; 631/250/2504/342; 631/80/39/2348; 631/80/642/333/1465; 692/4028/67/327; Acetoacetates - pharmacology; Acidosis; Acidosis, Lactic - drug therapy; Alternative fuels; Autophagy; Cancer; Cellular Reprogramming; Depolarization; Energy Metabolism; Gene Expression; Glycolysis; Humanities and Social Sciences; Humans; Hydrogen-Ion Concentration; Integrity; Lactic acid; Lactic Acid - metabolism; Lactic acidosis; Life Sciences; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Metabolic Engineering; Metabolism; Metabolites; Mitochondria; Mitochondria - metabolism; Mitophagy; Monocytes; multidisciplinary; Nutrient uptake; Phagocytosis; Protective Agents - pharmacology; Protons; Science; Science (multidisciplinary); Survival; Tissues; Tumor Microenvironment
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27426-x

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. Lactic acidosis is a metabolic state that occurs in injured tissues. Here the authors show that macrophages, in order to remain functional in acidosis, reduce their mitochondrial mass by mitophagy and rely on autophagy for survival, with mitochondrial integrity retained using acetoacetate as alternative fuel.