Diethyl Succinate Modulates Microglial Polarization and Activation by Reducing Mitochondrial Fission and Cellular ROS

Succinate is a metabolite in tricarboxylic acid cycle (TCA) which plays a central role in mitochondrial activity. Excess succinate is known to be transported out of cytosol where it activates succinate receptor (SUCNR1) to enhance inflammation in various contexts. However, the intracellular role of succinate beyond an intermediate metabolite and prior being released extracellularly, is not well characterized. Lipopolysaccharide (LPS) stimulates the elevation of intracellular succinate levels. To reveal the function of intracellular succinate associated with LPS stimulated inflammatory response in microglial cells, we assessed the levels of ROS, cytokines production and mitochondrial fission in primary microglia pretreated with cell-permeable diethyl succinate mimicking increased intracellular succinate. Our results suggest that elevated intracellular succinate exerts a protective role in primary microglia by preventing their conversion into the pro-inflammatory M1 phenotype induced by LPS. This protective effect is SUCNR1 independent and mediated by reducing mitochondrial fission and cellular ROS production.