SLC13 sodium-carboxylate transporters: function, regulation and pathophysiological implications in human disease

The SLC13 gene family encodes plasma membrane transporters with 11 putative transmembrane domains and comprises two functional subgroups: sodium-sulfate cotransporters (NaS) and sodium-carboxylate cotransporters (NaC). The NaC subfamily includes the low-affinity sodium-dicarboxylate cotransporter 1 (NaDC1/SLC13A2), the high-affinity sodium-dicarboxylate cotransporter 3 (NaDC3/SLC13A3) and the sodium-dependent citrate transporter (NaCT/SLC13A5), which facilitate the cellular uptake of tricarboxylic acid cycle (TCA) intermediates such as citrate, succinate and α-ketoglutarate. These substrates serve dual roles as metabolic fuels and signaling molecules. This review synthesizes recent advances in the structural biology, substrate specificity, tissue distribution, and regulation of NaC transporters, and highlights their emerging pathophysiological significance. Dysregulation of NaC transporters contributes to various human diseases, including metabolic disorders (e.g., nephrolithiasis and fatty liver disease), neurological conditions, and cancer. Elucidating the molecular mechanisms governing the function of NaC transporters is crucial for understanding disease etiology and developing targeted therapeutic strategies.