Citrate as metabolite
Citrate and iso-citrate are intermediates in the tricarboxylic acid (TCA) cycle in mitochondria and bacteria. In mitochondria, citrate synthase produces citrate from oxaloacetate (OAA) and acetyl-CoA. Citrate can be transported from mitochondria to cytosol by citrate carrier (CIC) to restore OAA and acetyl-CoA. Acetyl-CoA can be used for synthesis of fatty acids and for histone acetylation. OAA can be converted into pyruvate or lactate. Citrate inhibits glycolysis and TCA cycle, and stimulates gluconeogenesis and lipid synthesis. During inflammation, activated macrophages downregulate TCA cycle and direct citrate from ATP production into cytosol for production of prostaglandin and, via NADPH, production of NO and reactive oxygen species. In cancer cells, CIC is upregulated and citrate is directed from mitochondria to cytosol for anabolic processes.
Concentration of citrate in plasma is maintained at ∼100-150 µM, independent on the dietary intake. The pKa values of citric acid are 2.9, 4.3, and 5.6, and in the blood it exists as citrate. Cell membranes are impermeable to citrate, except via citrate transporters. Cancer cells may have upregulated the plasma membrane citrate transporter (variant of SLC25A1), supporting their metabolic needs (Mycielska et al., 2009 and 2018). About 90% of the total citrate in the body is in the bones, which function as a major reservoir of citrate. In the bone, citrate is synthesized and excreted by osteoblasts, and it is an important component (1%) of bone apatite crystals. Citrate is released to into plasma during bone resorption.
Astrocytes in the central nervous system (CNS) produce and release citrate, and citrate is found in cerebrospinal fluid (CSF) in high concentration. Citrate chelates Ca2+, Mg2+, Zn2+, and other metal cations, which make citrate an endogenous modulator of glutamate receptors (Westergaard et al., 2017).
Prostate produces and secretes citrate, using glucose and aspartate as substrates. Oxidation of citrate in mitochondria of the prostate cells is inhibited by high concentration of zinc. In prostate cancer citrate production can be reduced.
Citrate can be excreted into urine and oxidized in cells, mainly in the kidneys, the liver, and skeletal muscle. Impairment of citrate metabolism can lead to accumulation of citrate and calcium-citrate complex, hypocalcaenemia, hypomagnesaemia, and metabolic acidosis.
Citrate is a chelating agent for di- and trivalent metal ions (Me2+, Me3+). Sodium citrate is used as blood anticoagulant in processing of blood sampling and during haemofiltration and haemodialysis, because citrate chelates Ca2+ which is an essential component in blood clotting cascade. The risk of hypocalcaenemia and hypomagnesaemia is low, because citrate is metabolized in a the kidneys, the liver, and skeletal muscle, and calcium and magnesium are subsequently released back into the circulation. In renal tubular fluid and urine citrate keeps Ca2+ in soluble form, preventing it from crystallization as calcium oxalate and phosphate and forming kidney stones. Calcium sensing receptor (CaSR) in tubular system regulates citrate transport via dicarboxylate transporter NaDC1 from tubular fluid.
Many bacteria produce siderophore molecules, with citrate at their core, to pick iron from their environment. In addition to Fe3+, the same mechanism is at least partially responsible for uptake of 68Ga3+ in bacteria (Petrik et al., 2017).
Citrate binds iron ions, and albumin binds both iron ions and citrate. This facilitates Fe3+ binding to transferrin, reducing production of reactive oxygen species and oxidative stress (Matias et al., 2017). Ferric citrate supplementation is used to increase iron stores and haemoglobin, and it decreases serum phosphate levels, and is therefore used in treatment of dialysis and CKD patients.
After intravenous administration of [52Fe]citrate, 52Fe3+ is quickly bound to transferrin in the plasma. In the brain tumours, 52Fe uptake (administered as citrate) reflects the status of the BBB, and not the number of transferrin receptors (Roelcke et al., 1996). Uptake into normal brain is low but measurable (Calonder et al., 1999; Bruehlmeyer et al., 2000).
Iacobazzi V, Infantino V. Citrate - new functions for an old metabolite. Biol Chem. 2014; 395(4): 387-399. doi: 10.1515/hsz-2013-0271.
Updated at: 2019-01-23
Created at: 2018-09-30
Written by: Vesa Oikonen