The mitochondrial citrate carrier: a new player in inflammation

The mitochondrial citrate carrier (CIC) catalyzes the export of citrate from the mitochondrial matrix in exchange for cytosolic malate. In the cytosol the citrate is cleaved to acetyl-CoA and oxaloacetate by citrate lyase. Acetyl-CoA is directly used for fatty acid synthesis, and oxaloacetate produces NADPH + H+ also necessary for fatty acid production. Ever since its first functional characterization CIC role has been closely related to the liver metabolism. Recently, it is reported that CIC can also control glucose-stimulated insulin secretion. Our results suggest a new significant role of CIC in immune cells, where it has never been seen before. Therefore, CIC activity controls three fundamental inflammatory reactions, such as NO, ROS and PGE2 production, in a unique upstream step. Indeed, we display that CIC is essential in the synthesis of these inflammatory mediators in macrophages. Moreover, we demonstrate that BTA, a specific CIC inhibitor, strongly reduces NO, ROS and PGE2 levels. This means that CIC could be a new more powerful target of inflammation than the old ones because CIC inhibition prevents the spread of the inflammatory cascade at three different levels simultaneously. Finally, to clarify the molecular mechanisms responsible for CIC gene activation during inflammation we have performed in silico analysis of the human CIC gene promoter and we have found two NF-kB responsive elements. NF-kB binding site activity has been tested by luciferase gene reporter assay in the presence or absence of TPCK, a specific NF-kB inhibitor. Our data show that the increased CIC gene expression in immune cells is mediated by NF-kB.