{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC13A2 encodes the Na⁺‐dicarboxylate cotransporter‐1 (NaDC1), a plasma membrane protein that mediates the electrogenic, sodium‐dependent uptake of dicarboxylates (e.g., succinate) and tricarboxylates (e.g., citrate) across epithelial cells. Although a closely related transporter (NaCT) in the same SLC13 family shows high citrate selectivity in liver (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]), NaDC1 is predominantly expressed in the renal proximal tubule – as demonstrated by EGFP fusion and immunohistochemical studies – where its apical localization supports efficient reabsorption of citric acid cycle intermediates that are critical both for cellular energy generation and for maintaining acid–base homeostasis (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]). Additionally, functional studies reveal that NaDC1 exhibits substrate specificity that, while including citrate, extends to other dicarboxylates, underscoring its versatile role in metabolic flux (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, extensive structure–function analyses have revealed that key residues residing in transmembrane segments and adjacent extracellular loops are essential for both sodium and substrate binding. Site‐directed mutagenesis and modeling approaches have delineated ion binding sites and conformational states—consistent with an “elevator” mechanism—that govern transport kinetics (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", [."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, NaDC1 protein processing and trafficking are modulated by regulatory factors; for instance, cyclophilin B has been implicated as a chaperone partner in the modulation of transporter expression in response to cyclosporin A, while naturally occurring nonsynonymous SNPs have been shown to alter cation affinity and substrate selectivity (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, NaDC1 plays a pivotal role in determining urinary citrate levels—a key factor influencing kidney stone formation. Polymorphisms in the SLC13A2 gene have been linked to altered transporter kinetics and expression, correlating with variations in urinary citrate excretion and thus predisposing affected individuals to hypocitraturia and nephrolithiasis (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "]). In addition, population and review studies have further established that decreased NaDC1-mediated reabsorption and synergistic interactions with other transporter systems, such as SLC26A6, contribute to the metabolic imbalances underlying calcium oxalate kidney stone formation, insights that are now being enhanced by high-resolution structural analyses using cryo-electron microscopy (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Katsuhisa Inoue, Lina Zhuang, Vadivel Ganapathy "}, {"type": "b", "children": [{"type": "t", "text": "Human Na+ -coupled citrate transporter: primary structure, genomic organization, and transport function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(02)02669-4"}], "href": "https://doi.org/10.1016/s0006-291x(02"}, {"type": "t", "text": "02669-4) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12445824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12445824"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xueyuan Bai, Xiangmei Chen, Zhe Fen, et al. 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