SLC13A2

SLC13A2 (NaDC-1) is an electrogenic Na⁺-dicarboxylate cotransporter that reabsorbs citrate and succinate across the apical membrane of renal proximal tubule cells with a stoichiometry of ≥3 Na⁺ per substrate, and imports citrate into hepatocytes to fuel acetyl-CoA-dependent metabolic and epigenetic programs (PMID:8596711, PMID:27927654, PMID:39824985). Key determinants of cation and substrate recognition reside in transmembrane helices 8–9 (Asp-373, Glu-475) and the cytoplasmic end of TM3 (Lys-84), while PKC activation inhibits transport through partial endocytosis and direct activity suppression (PMID:10360950, PMID:10970779, PMID:10446305). Acid stimulation of NaDC-1 activity operates through two parallel pathways—an endothelin B receptor pathway and a Pyk2/c-Src → Raf1-ERK1/2-p90RSK kinase cascade—and is reciprocally modulated by physical interaction with SLC26A6 via the NaDC-1 first intracellular loop (PMID:20703215, PMID:29678998, PMID:23833257). In the liver, SLC13A2-imported citrate drives ACLY-dependent acetyl-CoA production that supports SREBP2-mediated cholesterol biosynthesis during regeneration and, in hepatocellular carcinoma, promotes PKM2 acetylation/degradation and histone acetylation to suppress tumor growth (PMID:39824985, PMID:41950310).

1. 1996 High

   Establishing the basic transport identity of SLC13A2: heterologous expression demonstrated that NaDC-1 is an electrogenic Na⁺-coupled cotransporter for di- and tricarboxylates with ~3 Na⁺ per succinate and pH-dependent citrate selectivity, defining its role as the apical renal citrate/succinate reabsorption pathway.

   Evidence Transient expression in COS-7 cells with radiolabeled substrate uptake and kinetic analysis

   PMID:8596711

   Open questions at the time

   • Three-dimensional structure undetermined
   • In vivo physiological confirmation not yet performed
   • Coupling stoichiometry for citrate not precisely defined
2. 1999 High

   Identification of the molecular determinants of cation and substrate recognition: systematic mutagenesis revealed that Asp-373 and Glu-475 in TM8–TM9 form part of the Na⁺/substrate binding site, Lys-84 at the cytoplasmic end of TM3 contributes to substrate affinity, and His-106 is required for membrane stability rather than catalysis, mapping functional residues onto the NaDC-1 topology.

   Evidence Site-directed mutagenesis of histidines, cysteines, and charged residues expressed in Xenopus oocytes with transport kinetics, electrophysiology, and surface biotinylation

   PMID:10360950 PMID:10548552 PMID:10970779 PMID:9512488

   Open questions at the time

   • No crystal or cryo-EM structure to confirm spatial arrangement of identified residues
   • Na⁺ binding order and cooperativity mechanism unresolved
3. 1999 High

   Discovery of acute post-translational regulation: PKC activation suppresses NaDC-1 transport by ~95% through a dual mechanism—partial endocytosis (~30% surface protein reduction) plus direct inhibition of remaining surface transporters—independent of PKC consensus sites on NaDC-1 itself.

   Evidence PMA/DOG treatment of NaDC-1-expressing Xenopus oocytes with transport assay, surface protein quantification, cytochalasin D, and staurosporine blockade

   PMID:10446305

   Open questions at the time

   • Direct PKC phosphorylation target mediating the ~65% non-endocytic inhibition is unknown
   • Physiological trigger for PKC-mediated regulation in vivo not established
4. 2004 High

   Acid regulation of NaDC-1 was shown to operate post-transcriptionally: media acidification stimulated citrate transport without changing NaDC-1 mRNA, complementing in vivo evidence that chronic metabolic acidosis increases apical NaDC-1 protein abundance in rat proximal tubule, revealing both transcriptional and post-transcriptional regulatory tiers.

   Evidence In vivo rat acidosis model with immunohistochemistry and mRNA quantification; OKP cell acidification with [14C]-citrate uptake and GFP-NaDC-1 trafficking

   PMID:10886565 PMID:14973148

   Open questions at the time

   • Post-transcriptional mechanism (trafficking vs. translational vs. stability) not molecularly defined
   • Whether acid regulation involves the same pathway in human kidney is untested
5. 2010 High

   The endothelin B receptor was identified as a required upstream mediator of acid-stimulated NaDC-1 activity: ETB knockout mice lost the acid-induced increase in brush border NaDC-1 activity, and the ETB C-terminal tail and transmembrane domain were required for ET-1-mediated stimulation.

   Evidence ETB knockout mouse, chimeric ETB receptor constructs in OKP cells, [14C]-citrate uptake, BQ788 antagonist

   PMID:20703215

   Open questions at the time

   • Whether ETB directly signals to NaDC-1 or acts through intermediate effectors was unknown at this stage
   • Relationship between ETB pathway and PKC inhibitory pathway not clarified
6. 2013 High

   NaDC-1 was shown to be reciprocally regulated by direct physical interaction with the oxalate transporter SLC26A6: the STAS domain of SLC26A6 binds the first intracellular loop of NaDC-1, SLC26A6 inhibits NaDC-1 activity in an activity-dependent manner, and NaDC-1 enhances SLC26A6 transport, linking citrate and oxalate homeostasis.

   Evidence Co-expression in Xenopus oocytes, domain mapping, Slc26a6-null mouse model

   PMID:23833257

   Open questions at the time

   • Structural basis of the STAS–intracellular loop interaction is unknown
   • In vivo consequences for kidney stone formation not directly tested
   • Whether other SLC26 family members similarly regulate NaDC-1 is unexplored
7. 2016 Medium

   Human tissue localization confirmed that NaDC-1 protein is restricted to the apical membrane along the entire proximal tubule and is absent from other nephron segments and renal tumors, solidifying its role as the sole apical dicarboxylate transporter in human kidney.

   Evidence Immunohistochemistry and immunoblot with NBCe1 colocalization in human kidney tissue sections

   PMID:27927654

   Open questions at the time

   • Single study with one antibody; independent antibody validation not reported
   • Functional transport data from human proximal tubule cells not included
8. 2018 High

   The intracellular signaling cascade for acid-stimulated NaDC-1 was delineated: Pyk2 and c-Src kinases activate Raf1-ERK1/2-p90RSK to stimulate NaDC-1 activity, and this cascade operates in parallel to (not downstream of) the ETB receptor pathway, as shown by Pyk2-null mice failing to upregulate NaDC-1 upon acid loading.

   Evidence Kinase inhibitors, Pyk2 knockdown/knockout mice, [14C]-citrate uptake in OKP cells, phospho-immunoblots for ERK1/2, Raf1, p90RSK

   PMID:29678998

   Open questions at the time

   • How p90RSK mechanistically increases NaDC-1 surface expression or activity is unknown
   • Integration point between ETB and Pyk2 pathways remains undefined
9. 2025 High

   A hepatic function for SLC13A2 was established: citrate imported by SLC13A2 in hepatocytes fuels ACLY-dependent acetyl-CoA production, SREBP2 cleavage, and de novo cholesterol biosynthesis, which is required for liver regeneration after partial hepatectomy.

   Evidence Liver-specific SLC13A2 overexpression/depletion in mice, partial hepatectomy, lovastatin and ACLY inhibitor epistasis, metabolic flux analysis

   PMID:39824985

   Open questions at the time

   • Whether SLC13A2 is the dominant citrate importer in hepatocytes or acts redundantly with other carriers is untested
   • Transcriptional or post-translational regulation of hepatic SLC13A2 during regeneration not characterized
10. 2026 High

    SLC13A2 was identified as a metabolic tumor suppressor in hepatocellular carcinoma: citrate-derived acetyl-CoA acetylates PKM2, triggering its degradation and suppressing glycolysis, amino acid, and nucleotide metabolism; simultaneously, increased histone acetylation provides an epigenetic basis for transcriptional suppression of tumor programs.

    Evidence AAV liver-specific knockout/overexpression in HCC mouse models, metabolic flux analysis, PKM2 acetylation assay, histone acetylation profiling, human tissue validation

    PMID:41950310

    Open questions at the time

    • Specific acetyltransferase(s) mediating PKM2 acetylation downstream of SLC13A2 not identified
    • Histone marks and target gene programs driven by SLC13A2-dependent acetylation not fully mapped
    • Whether SLC13A2 loss is a driver event in human HCC or a consequence of tumor metabolism is correlative

• Key unresolved questions include the three-dimensional structure of NaDC-1, the direct phosphorylation target mediating PKC-dependent transport inhibition, the integration point between the ETB and Pyk2/c-Src signaling arms, and the full spectrum of acetylation targets downstream of SLC13A2-imported citrate in liver.
• No high-resolution structure available
• Direct kinase substrate linking p90RSK to NaDC-1 activation unknown
• Relative contribution of SLC13A2 vs. other citrate carriers in hepatocytes not quantified