SLC16A10

SLC16A10 (MCT10/TAT1) is a facilitated-diffusion uniporter that bidirectionally equilibrates aromatic amino acids (phenylalanine, tyrosine, tryptophan) across epithelial plasma membranes, where it localizes to the basolateral membrane of small-intestine enterocytes and kidney proximal-tubule cells and to the sinusoidal side of perivenous hepatocytes (PMID:16245314). Genetic ablation in mice elevates plasma, muscle, and kidney aromatic amino acid levels and causes aromatic aminoaciduria under high-protein diet, establishing the transporter as required for net basolateral efflux from intestine and kidney and for hepatocyte-mediated control of extracellular aromatic amino acid concentrations (PMID:23045339). The same carrier transports the thyroid hormones T3 and T4: it mediates hormone efflux from liver, kidney, and thyroid and participates in tissue-specific thyroid hormone homeostasis, acting in genetic epistasis with the related transporter MCT8 (PMID:24248460, PMID:21315799). By facilitating T3 efflux, MCT10 chiefly governs peripheral T3 availability—potently feeding cell-surface type-3-deiodinase metabolism rather than steady-state nuclear receptor activation (PMID:27492966). Cryo-EM of human MCT10 in inward-facing and thyroxine-bound states defines a conserved gate-residue network that drives an alternating-access mechanism for hormone translocation and release. Through these transport functions MCT10 supports thyroid-hormone delivery to the cochlea, where loss alongside MCT8 produces hypothyroid-like sensory-epithelium defects rescued by T3 (PMID:29535325), maintains canonical basolateral TSH-receptor localization in thyrocytes (PMID:34071318), regulates fast-twitch muscle gene programs as a direct Six1 target (PMID:34809717), modulates bone mass (PMID:34669927), and promotes melanogenesis by importing phenylalanine into melanocytes (PMID:39171634).

1. 2006 High

   Established the molecular identity and transport mode of TAT1, answering whether SLC16A10 is an active or facilitative carrier and where it acts in epithelia.

   Evidence Xenopus oocyte transport assays with symmetrical influx/efflux kinetics plus immunolocalization in mouse intestine, kidney, and liver

   PMID:16245314

   Open questions at the time

   • Did not define physiological consequence of transport in vivo
   • Thyroid hormone handling not addressed
2. 2011 Medium

   Demonstrated that MCT10 transports iodothyronines and recognizes substrates differently from MCT8, extending its substrate range beyond amino acids.

   Evidence Radiolabeled BrAc-T3 transport and covalent-labeling assays in transfected cells with iodothyronine derivative inhibition

   PMID:21315799

   Open questions at the time

   • No structural basis for distinct substrate recognition
   • In vivo relevance of TH transport not yet tested
3. 2012 High

   Showed that TAT1 is physiologically required for aromatic amino acid homeostasis, converting in vitro transport activity into an organismal function.

   Evidence Knockout mouse phenotyping with plasma/tissue amino acid measurement and ex vivo everted gut sac efflux assays

   PMID:23045339

   Open questions at the time

   • Did not address thyroid hormone phenotypes
   • Mechanism of hepatocyte sink function not dissected at transporter level
4. 2013 High

   Resolved the in vivo contribution of MCT10 to thyroid hormone efflux and its genetic interaction with MCT8 in tissue-specific TH homeostasis.

   Evidence Mct10 single and Mct10/Mct8 double knockout mice with serum and tissue TH measurements

   PMID:24248460

   Open questions at the time

   • Tissue-level molecular mechanism of partial Mct8 rescue not defined
   • Did not separate amino acid from TH transport contributions
5. 2016 Medium

   Clarified where MCT10-mediated T3 transport exerts its effect, distinguishing peripheral T3 availability from nuclear receptor activation.

   Evidence JEG3 cell TRβ1/luciferase reporter, D3 metabolism assays, and CRYM co-transfection

   PMID:27492966

   Open questions at the time

   • Single cell-line model
   • Did not test endogenous tissue contexts
6. 2017 Medium

   Mapped a residue in the substrate trajectory by showing a natural SNP abolishes transport, linking sequence variation to carrier function.

   Evidence Yeast tat2Δ complementation tryptophan-uptake assay with N81K mutagenesis and HEK293T localization control

   PMID:28754537

   Open questions at the time

   • Physiological consequence of N81K in humans unknown
   • Single residue tested without full structural context
7. 2018 High

   Demonstrated that MCT10 with MCT8 delivers thyroid hormone to cochlear tissue, explaining a sensory phenotype mechanistically through TH.

   Evidence Mct8/Mct10 double knockout auditory testing, cochlear histology, and T3 rescue

   PMID:29535325

   Open questions at the time

   • Relative contribution of MCT10 versus MCT8 in cochlea not separated
   • Cell-type-specific transport site within cochlea undefined
8. 2021 Medium

   Linked MCT10 to thyrocyte membrane organization, showing it maintains canonical basolateral TSH-receptor localization.

   Evidence Immunofluorescence localization across Mct10, Ctsk, and Mct8 compound knockout thyroid tissue

   PMID:34071318

   Open questions at the time

   • Molecular mechanism connecting transport to TSHR trafficking unknown
   • Cathepsin K interaction mechanism not resolved
9. 2021 Medium

   Identified an upstream transcriptional regulator and a muscle-specific role, placing Slc16a10 in a Six1-driven fast-twitch gene program.

   Evidence ChIP genome-wide location analysis, in vivo RNAi, and TH-dependent reporter assay in tibialis anterior

   PMID:34809717

   Open questions at the time

   • Whether muscle effect is mediated by TH or amino acid transport not resolved
   • Single muscle model
10. 2022 Medium

    Revealed a site- and age-dependent role for MCT10 in bone mass through effects on osteoblast differentiation.

    Evidence MicroCT of Mct10 KO mice at multiple ages with osteoblast/osteoclast counts and in vitro differentiation assays

    PMID:34669927

    Open questions at the time

    • Transported substrate driving bone phenotype not identified
    • Mechanism for biphasic age-dependent effect unknown
11. 2024 Medium

    Established a melanogenic function by showing SLC16A10 imports phenylalanine to drive melanin synthesis.

    Evidence Overexpression/knockdown in MNT1 melanocytes with melanin quantification, targeted metabolomics, ELISA, and UVB model

    PMID:39171634

    Open questions at the time

    • How phenylalanine uptake increases TYR/TYRP1 protein without RNA change unclear
    • Single cell-line system
12. 2024 Medium

    Placed SLC16A10 in an inflammatory regulatory circuit as a direct miR-21-5p target controlling LPS-induced cytokine output.

    Evidence Dual-luciferase reporter, siRNA knockdown, and miR-21-5p mimic/inhibitor rescue in A549 cells

    PMID:38750066

    Open questions at the time

    • Transport mechanism linking SLC16A10 to cytokine induction undefined
    • Single epithelial cell line
13. 2024 High

    Defined the structural basis of thyroid hormone transport, revealing the alternating-access gate mechanism.

    Evidence Cryo-EM of human MCT10 in inward-facing and thyroxine-bound states (preprint)

    Open questions at the time

    • Outward-facing state not captured
    • Aromatic amino acid bound structures not determined

• How the single transporter's distinct substrate streams (aromatic amino acids versus thyroid hormones) are integrated to produce its diverse tissue-specific phenotypes remains unresolved.
• No human disease mutation has been linked to SLC16A10 via direct genetic evidence in this corpus
• Substrate selectivity determinants between amino acids and iodothyronines not structurally separated
• Regulatory partners coordinating transport with downstream phenotypes largely undefined