citrate transporter

The citrate carrier (CiC), characteristic of animals, and the dicarboxylate–tricarboxylate carrier (DTC), characteristic of plants and protozoa, belong to the mitochondrial carrier pro- tein family whose members are responsible for the exchange of metabolites, cofactors, and nucleotides between the cyto- plasm and the mitochondrial matrix. Most of the functional data on these transporters are obtained from the studies per- formed with the protein purified from rat, eel yeast, and maize mitochondria or recombinant proteins from different sources incorporated into phospholipid vesicles (liposomes). The func- tional data indicate that CiC is responsible for the efflux of acetyl-CoA from the mitochondria to the cytosol in the form of citrate, the primer for fatty acid, cholesterol synthesis, and his- tone acetylation. Like the CiC, the citrate exported by DTC
from the mitochondria to the cytosol in exchange for oxaloac- etate can be cleaved by citrate lyase to acetyl-CoA and oxalo- acetate and used for fatty acid elongation and isoprenoid synthesis. In addition to its role in fatty acid synthesis, CiC is involved in other processes such as gluconeogenesis, insulin secretion, inflammation, and cancer progression, whereas DTC is involved in the production of glycerate, nitrogen assimila- tion, ripening of fruits, ATP synthesis, and sustaining of respi- ratory flux in fruit cells. This review provides an assessment of the current understanding of CiC and DTC structural and biochemical characteristics, underlying the structure–function relationship of these carriers. Furthermore, a phylogenetic relationship between CiC and DTC is proposed.

Background: The most common microdeletion congenital disorder, 22qDS, is the second risk factor for schizophrenia. Results: Plasma metabolomics in 22qDS consisted of an oxidative phosphorylation-to-glycolysis shift with altered 2-hydroxyglutaric acid, cholesterol, and fatty acid concentrations. Conclusion: Despite the haploinsufficiency of ϳ30 genes, the 22qDS metabolic signature chiefly reflected deficits in the mitochondrial citrate transporter. Significance: Biochemical profiling of 22qDS unveiled the impact of SLC25A1 haploinsufficiency.

SLC13A5 is a Na +-coupled transporter for citrate that is expressed in the plasma membrane of specific cell types in the liver, testis, and brain. It is an electrogenic transporter with a Na + :citrate 3− stoichiometry of 4:1. In humans, the Michaelis constant for SLC13A5 to transport citrate is ~600 µM, which is physiologically relevant given that the normal concentration of citrate in plasma is in the range of 150–200 µM. Li + stimulates the transport function of human SLC13A5 at concentrations that are in the therapeutic range in patients on lithium therapy. Human SLC13A5 differs from rodent Slc13a5 in two important aspects: the affinity of the human transporter for citrate is ~30-fold less than that of the rodent transporter, thus making human SLC13A5 a low-affinity/high-capacity transporter and the rodent Slc13a5 a high-affinity/low-capacity transporter. In the liver, SLC13A5 is expressed exclusively in the sinusoidal membrane of the hepatocytes, where it plays a role in the uptake of circulating citrate from the sinusoidal blood for metabolic use. In the testis, the transporter is expressed only in spermatozoa, which is also only in the mid piece where mitochondria are located; the likely function of the transporter in spermatozoa is to mediate the uptake of citrate present at high levels in the seminal fluid for subsequent metabolism in the sperm mitochondria to generate biological energy, thereby supporting sperm motility. In the brain, the transporter is expressed mostly in neurons. As astrocytes secrete citrate into extracellular medium, the potential function of SLC13A5 in neurons is to mediate the uptake of circulating citrate and astrocyte-released citrate for subsequent metabolism. Slc13a5-knockout mice have been generated; these mice do not have any overt phenotype but are resistant to experimentally induced metabolic syndrome. Recently however, loss-of-function mutations in human SLC13A5 have been found to cause severe epilepsy and encephalopathy early in life. Interestingly, there is no evidence of epilepsy or encephalopathy in Slc13a5-knockout mice, underlining the significant differences in clinical consequences of the loss of function of this transporter between humans and mice. The markedly different biochemical features of human SLC13A5 and mouse Slc13a5 likely contribute to these differences between humans and mice with regard to the metabolic consequences of the transporter deficiency. The exact molecular mechanisms by which the functional deficiency of the citrate transporter causes epilepsy and impairs neuronal development and function remain to be elucidated, but available literature implicate both dysfunction of GABA (γ-aminobutyrate) signaling and hyperfunction of NMDA (N-methyl-D-aspartate) receptor signaling. Plausible synaptic mechanisms linking loss-of-function mutations in SLC13A5 to epilepsy are discussed.