Identification of Monocarboxylate Transporter 8 as a Specific Thyroid Hormone Transporter

Friesema, Edith C. H.; Ganguly, Sumita; Abdalla, A. E. D.; Fox, Jocelyn E. Manning; Halestrap, Andrew P.; Visser, Theo J.

doi:10.1074/jbc.m300909200

Cited by 615 publications

(443 citation statements)

References 27 publications

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“…This finding is nevertheless noteworthy, as it implies that the methionine considered to mark the translation start in NM_006517 19,20 is likely not the relevant translation start codon and therefore provides evidence sustaining the earlier suggestion that another methionine at position p.75 might be the start codon for the MCT8 protein.…”

Section: Discussionmentioning

confidence: 49%

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

et al. 2008

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Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan -HerndonDudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores 42.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A4T and c.1673G4A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G4A showed elevated serum T3 level. The c.1A4T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A4T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together, these data indicate that MCT8 mutations are not common in non-AHDS MR patients yet they support that elevated serum T3 levels can be indicative for AHDS and that AHDS clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation.

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Section: Discussionmentioning

confidence: 49%

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

et al. 2008

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“…125 I]T 3 -The only substrates of MCT8 so far identified are iodothyronines (4). A large number of iodothyronines and related molecules are available to probe structural determinants for transport by MCT8.…”

Section: Structural Determinants Of Substrate Molecules Determined Bymentioning

confidence: 99%

“…Several classes of transmembrane transporter proteins of the major facilitator superfamily (MFS) are capable of TH transport; organic anion transporters two and three (Oatp2 and Oatp3) were the first TH transporters cloned (2). Later, L-type amino acid transporters (Lat1, Lat2) (3) and monocarboxylate transporters eight and ten (MCT8 and MCT10) were shown to transport TH (4,5). Among these transporters, only MCT8 is specific for TH.…”

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confidence: 99%

“…Mutations in MCT8/SLC16A2 lead to severe psychomotor retardation and TH abnormalities in humans (6,7), including the Allan-Herndon-Dudley Syndrome (8). Patients suffering from mutations in MCT8 are characterized by high serum T 3 values associated with low T 4 and inappropriately normal thyroid-stimulating hormone. This clinical phenotype suggested that MCT8 is involved in pituitary feedback control of the TH axis.…”

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confidence: 99%

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Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

Kinne

Kleinau

Hoefig

et al. 2010

Journal of Biological Chemistry

102

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Monocarboxylate transporter 8 (MCT8, SLC16A2) is a thyroid hormone (TH) transmembrane transport protein mutated in Allan-Herndon-Dudley syndrome, a severe X-linked psychomotor retardation. The neurological and endocrine phenotypes of patients deficient in MCT8 function underscore the physiological significance of carrier-mediated TH transmembrane transport. MCT8 belongs to the major facilitator superfamily of 12 transmembrane-spanning proteins and mediates energy-independent bidirectional transport of iodothyronines across the plasma membrane. Structural information is lacking for all TH transmembrane transporters. To gain insight into structure-function relations in TH transport, we chose human MCT8 as a paradigm. We systematically performed conventional and liquid chromatography-tandem mass spectrometrybased uptake measurements into MCT8-transfected cells using a large number of compounds structurally related to iodothyronines. We found that human MCT8 is specific for L-iodothyronines and requires at least one iodine atom per aromatic ring. Neither thyronamines, decarboxylated metabolites of iodothyronines, nor triiodothyroacetic acid and tetraiodothyroacetic acid, TH derivatives lacking both chiral center and amino group, are substrates for MCT8. The polyphenolic flavonoids naringenin and F21388, potent competitors for TH binding at transthyretin, did not inhibit T 3 transport, suggesting that MCT8 can discriminate its ligand better than transthyretin. Bioinformatic studies and a first molecular homology model of MCT8 suggested amino acids potentially involved in substrate interaction. Indeed, alanine mutation of either Arg 445 (helix 8) or Asp 498(helix 10) abrogated T 3 transport activity of MCT8, supporting their predicted role in substrate recognition. The MCT8 model allows us to rationalize potential interactions of amino acids including those mutated in patients with Allan-HerndonDudley syndrome.

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“…MCTs form a transmembrane protein family, which cotransport a proton together with a lactate anion. In addition to lactate, MCTs also facilitate the transport of other monocarboxylate anions, such as short chain fatty acids (SCFA) and ketone bodies, through cell membranes (Halestrap & Meredith, review 2004), and at least isoform 8 (MCT8) is also involved in the transport of thyroid hormones into cells (Friesema, Ganguly, Abdalla, Manning Fox, Halestrap, & Visser, 2003).…”

Section: Monocarboxylate Transportersmentioning

confidence: 99%

Carbohydrate metabolism in meat animals

2005

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Oxidative energy production is by far dominant in living animal muscles, with the exception the short periods of severe stress, where the aerobic capacity is exceeded, and formation of large amounts of lactic acid will take place. Energy consumption in muscle cells continues post mortem with formation of large amounts of lactate and formation of protons, because the aerobic processes for energy production are not available. Post mortem, the fall in pH is delayed only by buffering capacity of the muscle fibres. In living animals, in addition to buffering capacity, both respiration and transport of lactate and protons out of the muscle fibres by monocarboxylate transporters participate in the regulation of muscle fibre pH which never falls as low as the ultimate pH of the meat. Understanding the regulation of pH in muscle is important both for the welfare of living animals and from the technological point of view as a factor influencing meat quality.

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Identification of Monocarboxylate Transporter 8 as a Specific Thyroid Hormone Transporter

Cited by 615 publications

References 27 publications

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

Carbohydrate metabolism in meat animals

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