“The citrate-related inflammatory pathway”

The mitochondrial citrate carrier (CIC), encoded by the SLC25A1 gene, catalyses the export of citrate from the mitochondrial matrix to the cytosol, where it is cleaved to acetyl-CoA and oxaloacetate by ATP citrate lyase (ACLY). Acetyl-CoA is mainly used for fatty acid synthesis, and oxaloacetate produces NADPH + H+ also necessary for fatty acid production. Both CIC and ACLY enzymes are highly expressed in liver and play an essential metabolic role. Recently, we have identified their involvement in the inflammation pathway. Macrophages and U937 cells treated with lipopolysaccharide (LPS), tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ), show a significantly upregulation of SLC25A1 as well as ACLY through NFkB and STAT1 signaling pathways. We demonstrate that CIC and ACLY activity is required for ROS, nitric oxide and prostaglandins production. Importantly, we show that the citrate exported from mitochondria via CIC and its downstream metabolic intermediate, acetyl-coenzyme A, are necessary for TNFα or IFNγ-dependent inflammatory response. These findings highlight a “citrate pathway” involvement in pro-inflammatory signals and in inflammatory mediator production.