NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION | 1 Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Arturo Duperier 4, 28029 Madrid, Spain. (J.B., A.G.‑F.). Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Arturo Duperier 4, 28029 Madrid, Spain (B.M.). Correspondence to: J.B. jbernal@iib.uam.es Thyroid hormone transporters—functions and clinical implications Juan Bernal, Ana Guadaño-Ferraz and Beatriz Morte Abstract | The cellular influx and efflux of thyroid hormones are facilitated by transmembrane protein transporters. Of these transporters, monocarboxylate transporter 8 (MCT8) is the only one specific for the transport of thyroid hormones and some of their derivatives. Mutations in SLC16A2, the gene that encodes MCT8, lead to an X‑linked syndrome with severe neurological impairment and altered concentrations of thyroid hormones. Histopathological analysis of brain tissue from patients who have impaired MCT8 function indicates that brain lesions start prenatally, and are most probably the result of cerebral hypothyroidism. A Slc16a2 knockout mouse model has revealed that Mct8 is an important mediator of thyroid hormone transport, especially T 3 , through the blood–brain barrier. However, unlike humans with an MCT8 deficiency, these mice do not have neurological impairment. One explanation for this discrepancy could be differences in expression of the T 4 transporter OATP1C1 in the blood–brain barrier; OATP1C1 is more abundant in rodents than in primates and permits the passage of T 4 in the absence of T 3 transport, thus preventing full cerebral hypothyroidism. In this Review, we discuss the relevance of thyroid hormone transporters in health and disease, with a particular focus on the pathophysiology of MCT8 mutations. Bernal, J. et al. Nat. Rev. Endocrinol. advance online publication 5 May 2015; doi:10.1038/nrendo.2015.66 Introduction The thyroid hormones, T 4 (3,5,3',5'tetraiodo‑L‑ thyronine) and T 3 (3,5,3'tri‑iodo‑L‑thyronine; also known as tri‑iodothyronine) are iodinated amino acids produced and secreted by the thyroid gland. These hor‑ mones regulate many developmental and metabolic pro‑ cesses. The nuclear T 3 receptors are ligand‑modulated transcription factors encoded by two genes, THRA and THRB. These genes encode several receptor proteins, of which three (thyroid hormone receptor α1, thyroid hormone receptor β1 and thyroid hormone receptor β2) interact with T 3 , which results in tissue‑specific and developmentally‑dependent transcriptomic changes. 1 In the developing cerebral cortex, 500–1,000 genes are directly or indirectly affected by thyroid hormones. 2 In addition, both T 4 and T 3 perform nongenomic, extra‑ nuclear actions. For example, T 3 might interact with a plasma‑membrane‑associated thyroid hormone recep‑ tor α variant, 3 and with cytoplasmic thyroid hormone receptor β, 4 while T 4 interacts with integrin α v β 3 and acti‑ vates diverse signalling pathways such as the phospho‑ inositide 3‑kinase pathway and mitogen‑activated protein kinase pathways. 5,6 Metabolism of thyroid hormones includes the pro‑ cesses of deiodination, deamination, decarboxylation, sulphation and glucuronidation, which have been exten‑ sively reviewed elsewhere. 7 The most relevant pathway for the discussion in this Review is deiodination, a process that activates or inactivates thyroid hormones. Deiodinases are selenoproteins that catalyze the removal of specific iodine atoms from the phenolic or tyrosyl rings of the iodothyronine molecule. Type 1 iodothyronine deiodinase and type 2 iodothyronine deiodinase (DIO1 and DIO2, encoded by the DIO1 and DIO2 genes, respec‑ tively) have phenolic, or ‘outer’ ring, activity and convert T 4 to T 3 . 8 In extrathyroidal tissues, this pathway generates ~80% of the total body pool of T 3 . 9 Type 3 iodothyronine deiodinase (DIO3, encoded by the DIO3 gene) and DIO1 have tyrosyl, or ‘inner’ ring, activity and convert T 4 and T 3 to the inactive metabolites 3,3'5'‑triiodo‑L‑thyronine (rT 3 ) and 3,3'‑diiodo‑L‑thyronine (T 2 ), respectively; rT 3 is then further metabolized by DIO1 to T 2 . Until the 1970s, the passage of thyroid hormones through the cell membrane was thought to be a process of passive diffusion. 10 However, for uncharged molecules, the basal permeability of membranes decreases rapidly with size, and is low for molecules with a molecular weight >100. 11 A number of investigators described the presence of low affinity transport systems for thyroid hor‑ mones in tissues and cultured cells. 10 However, not until 2004, 12,13 when mutations in a gene encoding a previously identified cell membrane transporter for thyroid hormone were identified, was monocarboxylate transporter 8 (MCT8) 14,15 established as having pathophysiological relevance of thyroid hormone transport. Several proteins with overlapping specificity have the capacity to transport thyroid hormones across cell membranes, including the monocarboxylate trans‑ porters (MCT), organic anion transporter polypeptides (OATP), large neutral amino acid transporters (LAT) Competing interests The authors declare no competing interests. REVIEWS © 2015 Macmillan Publishers Limited. All rights reserved