Itaconic acid decreases mitochondrial respiration and ROS generation in brain tissue

Itaconic acid (IA) is a recently discovered mammalian metabolite which is produced by macrophages upon pro-inflammatory activation: in quiescent bone marrow – derived macrophages (BMDMs). IA is hardly detectable but upon lipopolysaccharide (LPS) stimulation it reaches millimolar concentrations [1]. Recently reported physiological roles of IA include inhibition of bacterial enzyme isocitrate lyase (bactericidal activity) and the inhibition of a Krebs cycle enzyme succinate dehydrogenase (SDH) in the host cells (which has been shown for BMDMs) [2,3]. By inhibiting SDH, IA regulates succinate (a pro-inflammatory metabolite) levels thus remodelling the host cells metabolism during inflammation [3]. Microglia are macrophages residing in the brain, however, it is not clear whether these cells can also produce IA. In general, there has been very little research on IA effects on brain tissue. Therefore, in this study, we investigated whether IA exerts an effect on brain mitochondrial respiration and ROS generation and whether IA is neurotoxic.