Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line
Moris Sangineto, Martina Ciarnelli, Archana Moola, Vidyasagar Naik Bukke, Tommaso Cassano, Rosanna Villani, Antonino Davide Romano, Giuseppe Di Gioia, Carlo Avolio, Gaetano Serviddio
Abstract
• LPS induces metabolic reprogramming in microglia, increasing glycolysis and mitochondrial respiration with oxidative stress. • Krebs cycle derivatives, dimethyl fumarate and itaconate, counteract LPS-induced cytokine production and metabolic rewiring. • Despite similar bioenergetic and anti-inflammatory effects, DMF and ITA modulate mitochondrial activity in a different way. Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglial clone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.