Significant metabolic changes occur in inflammation to respond to the new energetic needs of cells. Mitochondria are addressed not only to produce ATP, but also to supply substrates, such citrate, to produce pro-inflammatory molecules. In this context most of citrate is diverted from Krebs cycle and channeled into the "citrate pathway" consisting in the increase of the export of citrate into cytosol by the mitochondrial citrate carrier followed by its cleavage into acetyl-CoA and oxaloacetate by ATP citrate lyase. Acetyl-CoA is used to produce PGE2 and oxaloacetate to make NADPH needed for NO and ROS. In addition cytosolic citrate provides also for itaconate synthesis. Citrate-derived itaconate acts as a negative regulator of inflammation by modulating the synthesis of the inflammatory mediators. Inhibition of CIC or ACLY by different synthetic and natural molecules results in reduction of NO, ROS and PGE2 levels suggesting that the citrate pathway can be a new target to be addressed in inflammation. Beneficial effects can be obtained also in the oxidative stress and inflammatory conditions observed in Down syndrome.

Metabolic routes in inflammation: the citrate pathway and its potential as therapeutic target

Pierri, Ciro Leonardo;Iacobazzi, Vito
2018

Abstract

Significant metabolic changes occur in inflammation to respond to the new energetic needs of cells. Mitochondria are addressed not only to produce ATP, but also to supply substrates, such citrate, to produce pro-inflammatory molecules. In this context most of citrate is diverted from Krebs cycle and channeled into the "citrate pathway" consisting in the increase of the export of citrate into cytosol by the mitochondrial citrate carrier followed by its cleavage into acetyl-CoA and oxaloacetate by ATP citrate lyase. Acetyl-CoA is used to produce PGE2 and oxaloacetate to make NADPH needed for NO and ROS. In addition cytosolic citrate provides also for itaconate synthesis. Citrate-derived itaconate acts as a negative regulator of inflammation by modulating the synthesis of the inflammatory mediators. Inhibition of CIC or ACLY by different synthetic and natural molecules results in reduction of NO, ROS and PGE2 levels suggesting that the citrate pathway can be a new target to be addressed in inflammation. Beneficial effects can be obtained also in the oxidative stress and inflammatory conditions observed in Down syndrome.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/255034
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