Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line

[Display omitted] •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 microglialclone 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.