Regulation of leukocyte function by citric acid cycle intermediates

Abstract

Cellular metabolism is a means of generating ATP to provide energy for key cellular functions. However, recent research shows that citric acid cycle intermediates target vital cellular functions of the innate immune system. Succinate, itaconate, citrate, and fumarate have been shown to mediate or regulate important myeloid cell functions during infection and inflammation. This review covers the regulatory functions of citric acid cycle intermediates in myeloid cells and discusses potential translational applications, key mechanistic questions, and future research directions.

Keywords: citrate; fumarate; itaconate; metabolic reprogramming; succinate.

Figure 1.. Role of succinate and itaconate in modulating myeloid cell functions

Inflammatory activation on myeloid cells leads to accumulation of succinate and itaconate in the mitochondria. High oxidation levels of succinate in TCA cycle favors reverse electron transport, from complex II (CII or SDH) to complex I (CI), generating elevated mitochondrial reactive oxygen species (mROS). Mitochondrial succinate is transported into the cytosol, where it stabilizes HIF-1α along with mROS. HIF-1α acts to increase glycolysis and proinflammatory cytokine secretion including IL-1β and IL-6. Succinate also causes post-translational modification of proteins (succinylation). Succinate is also transported into extracellularly, where it can act on its receptor, SUCNR1, which further fuels inflammatory response. Citrate is diverted away from TCA cycle to produce Itaconate via immunoregulatory gene 1 (IRG1) enzyme through the intermediate, cis-aconitate. This is accomplished via a disruption in the TCA cycle at the level of α-ketoglutarate synthesis. Itaconate inhibits SDH and limits the proinflammatory effects of succinate. Itaconate is also transported into cytosol via an unknown carrier protein, where it activates Nrf2 via alkylation of Keap1. Itaconate can also be transported extracellularly via unknown mechanisms, where it can kill pathogens and improve microbial clearance. Aspartate arginosuccinate shunt fuels the TCA cycle through replenishing fumarate levels.

Figure 2.. Role of Citrate in metabolic reprogramming of myeloid cells

Citrate accumulates intracellularly upon myeloid cell activation. Accumulated citrate is transported into the cytosol via mitochondrial citrate carrier (CIC). In the cytosol, citrate is broken down into oxaloacetate and acetyl-CoA. Oxaloacetate is converted to malate via and malate is further converted to pyruvate leading to generation of NADPH as a by-product. NADPH is utilized by NADPH oxidase and inducible nitric oxide synthase to generate reactive oxygen and nitrogen species, and PGE2. The majority of accumulated pyruvate is transported back into the mitochondria to generate citrate for fueling the TCA cycle. Malate can also be transported back into the mitochondria later during inflammation to replenish mitochondrial stores of oxaloacetate and citrate. Furthermore, acetyl-CoA derived from citrate acts either to acetylate substrates or is utilized for fatty acid synthesis in the cytosol.