Language
English
Publication Date
10-2-2025
Journal
Cell
DOI
10.1016/j.cell.2025.06.032
PMID
40680733
PMCID
PMC12364305
PubMedCentral® Posted Date
7-17-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Adequate delivery of thyroid hormones to the brain is crucial for normal neurological development. MCT8 and OATP1C1, two solute carrier (SLC) transporters, mediate the passage of thyroid hormones across the blood-brain barrier and into the central nervous system. Mutations in MCT8 result in Allan-Herndon-Dudley syndrome (AHDS), an X-linked birth defect characterized by neurodevelopmental impairments and peripheral hyperthyroidism, whereas OATP1C1 deficiency is linked to brain hypometabolism and progressive neurodegeneration. Here, we report cryoelectron microscopy (cryo-EM) structures of MCT8 and OATP1C1 bound with the active thyroid hormone triiodothyronine (T3) and the prohormone thyroxine (T4) at 2.9 and 2.3 Å resolutions, respectively. Combined with functional studies, we elucidate their distinct thyroid hormone recognition and transport mechanisms and explain disease mutations. Although extracellular allosteric sites are not a common feature of SLC transporters, we identify one in OATP1C1. Collectively, these findings illuminate key aspects of thyroid hormone transport, a fundamental process in development and disease.
Keywords
Humans, Brain, Monocarboxylic Acid Transporters, Triiodothyronine, Cryoelectron Microscopy, Organic Anion Transporters, Thyroxine, X-Linked Intellectual Disability, Thyroid Hormones, Muscle Hypotonia, Biological Transport, Animals, Muscular Atrophy, Models, Molecular, Mutation, Amino Acid Transport Systems, Neutral, Blood-Brain Barrier, HEK293 Cells, Symporters
Published Open-Access
yes
Recommended Citation
Ge, Yunhui; Dou, Tongyi; Nguyen, Thu Uyen; et al., "Structural Insights Into Brain Thyroid Hormone Transport via MCT8 and OATP1C1" (2025). Faculty, Staff and Students Publications. 8348.
https://digitalcommons.library.tmc.edu/baylor_docs/8348