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

Clément Adam,Florence Manero,Laurence Preisser,Naïg Gueguen,Léa Paolini,Pascale Jeannin,Simon Blanchard,Vincent Procaccio,Morgane Le Mao,Alain Morel,Céline Beauvillain,Yves Delneste,Pascal Reynier,Pascale Pignon,Guillaume Mabilleau

doi:10.1038/s41467-021-27426-x

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.

Highlights

Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues
We investigated the mechanisms by which human monocytes cope with lactic acid (LA) by culturing monocytes with GM-CSF (Mφ) without or with 10 mM LA (LA-Mφ; pH = 6.5), the maximum non-toxic concentration for Mφ (Supplementary Fig. 1)
The residual mitochondria maintain a quite functional electron transport chain (ETC), as the part of the maximal capacity used for sustaining ATP synthesis is not significantly decreased in LA-Mφ compared to Mφ (Fig. 1b) and the complex IV activity normalized to citrate synthase activity was not affected (Fig. 1d)

Summary

Introduction

The extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. 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. Extracellular lactate concentrations, which range between 1.8 and 2 mM in resting tissues, can reach up to 20 mM in wounds, and 40 mM in solid tumors[6] Cells tightly control their intracellular pH, but prolonged extracellular acidosis can affect several aspects of cellular homeostasis, including metabolism, signaling, and transcriptional activities[7,8,9]. Experiments were conducted under atmospheric oxygen and in the presence of glucose, to rule out the effect of oxygen or glucose deprivation

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