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

Area of Science:

• Cellular metabolism
• Immunology
• Acidosis research

Background:

• Lactic acidosis, characterized by extracellular lactate and proton accumulation, arises from insufficient tissue oxygen supply.
• Monocytes differentiate into macrophages in acidotic conditions to resolve injury, but their metabolic state is affected.
• Key metabolic shifts in these cells include mitochondrial depolarization and reduced nutrient absorption.

Purpose of the Study:

• To investigate the metabolic adaptations of human monocytes differentiating into macrophages under lactic acidosis.
• To determine the role of extracellular pH versus lactosis in these metabolic changes.
• To explore the potential of acetoacetate as a metabolic fuel to mitigate acidosis-induced cellular stress.

Main Methods:

• Analysis of mitochondrial function and mass in differentiating human monocytes under lactic acidosis.
• Assessment of nutrient absorption and autophagy dependence in these cells.
• Evaluation of acetoacetate's impact on monocyte/macrophage metabolism and survival in vitro.

Main Results:

• Lactic acidosis induces a pseudostarvation state in differentiating monocytes, characterized by mitochondrial dysfunction and reduced nutrient uptake, driven by low extracellular pH.
• These metabolic changes increase cellular dependence on autophagy for survival.
• Acetoacetate utilization by monocytes/macrophages preserves mitochondrial integrity, nutrient uptake, and survival without autophagy, mitigating acidosis effects.

Conclusions:

• Low extracellular pH in lactic acidosis triggers pseudostarvation in differentiating monocytes, necessitating autophagy for survival.
• Acetoacetate serves as an alternative fuel source, maintaining cellular function and viability under lactic acidosis.
• Acetoacetate shows potential in enhancing tissue tolerance to sustained lactic acidosis.