DIO2

Last update 08 May 2025

Basic Info

Synonyms

5DII, deiodinase-2, deiodinase, iodothyronine type II

+ [13]

Introduction

Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine) into T3 (3,5,3'-triiodothyronine). Essential for providing the brain with appropriate levels of T3 during the critical period of development.

100 Clinical Results associated with DIO2

100 Translational Medicine associated with DIO2

0 Patents (Medical) associated with DIO2

1,299

Literatures (Medical) associated with DIO2

25 Apr 2025·Circulation Research

Local DIO2 Elevation Is an Adaption in Malformed Cerebrovasculature

Article

Author: Tang, Yushan ; Zhang, Yu ; Lv, Cheng ; Yu, Liang ; Hu, Pengyan ; Wang, Yibo ; Li, Ruofei ; Wang, Haiyue ; Gerdes, A. Martin

BACKGROUND:Cerebrovascular malformations are a pivotal cause of hemorrhage and neurological disability alongside lacking effective medication. Thyroid hormones (THs), including thyroxine and triiodothyronine, are essential for vascular development, yet whether they participate in malformed cerebrovascular pathology remains elusive.METHODS: Single-cell transcriptome analysis characterized human cerebral cavernous malformations and brain arteriovenous malformations, 2 typical cerebrovascular malformation diseases. Adeno-associated virus–mediated Dio2 (iodothyronine deiodinase 2; an enzyme that converts thyroxine to active triiodothyronine) overexpression/knockdown or triiodothyronine/methimazole (an antithyroid drug) treatment was applied to mouse models of cerebral cavernous malformations (endothelial-specific Pdcd10 knockout mice, Pdcd10 endothelial-specific knockout [KO]) and brain arteriovenous malformations (endothelial-specific KrasG12D mutant mice, KrasG12D ) to evaluate the involvement of DIO2 and TH signaling in cerebrovascular malformations. RESULTS: TH signaling was markedly activated in fibroblasts of human cerebral cavernous malformation and arteriovenous malformation single-cell samples, accompanied by elevated DIO2 expression. Similar DIO2 upregulation was observed in cerebrovascular fibroblasts of Pdcd10 KO/ KrasG12D mice and patient brain sections. Exogenous Dio2 or triiodothyronine replenishment effectively reduced brain hemorrhage, excessive ECM (extracellular matrix) remodeling, and vascular leakage in juvenile and adult male and female Pdcd10 KO/ KrasG12D mice. In contrast, Dio2 silencing or TH inhibition deteriorated vascular anomalies. Mechanistically, transcription factor FOXK1 (forkhead box K1) was determined to interact with the DIO2 promoter region. The activation of fibroblast PI3K (phosphoinositide 3-kinase)-Akt (protein kinase B)-mTOR (mammalian target of rapamycin) signaling in Pdcd10 KO/ KrasG12D mice triggered Foxk1 nuclear translocation to promote Dio2 transcription. Triiodothyronine treatment mitigated inflammatory infiltration, normalized mitochondrial morphology, and restored mitochondrial biogenesis in malformed brain vessels by activating the Pgc1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha)-Sod2 (superoxide dismutase 2)/Prdx3 (peroxiredoxin 3)/Gpx1 (glutathione peroxidase 1) axis to reduce reactive oxygen species accumulation. We also determined that the vascular repair effects of triiodothyronine were Pgc1a-dependent. CONCLUSIONS:We delineate a novel DIO2-mediated adaption in malformed cerebrovasculature and conclude that targeting TH signaling may represent a potential therapy for cerebrovascular disorders.

24 Mar 2025·Endocrinology

FVB But Not B6 Mice Carrying the Thr92Ala-Dio2 Polymorphism Have Impaired Thyroid Hormonogenesis and Goiter

Article

Author: Arvan, Peter ; Salas-Lucia, Federico ; Bianco, Antonio C ; Ribeiro, Miriam O ; McAninch, Elizabeth A ; Bocco, Barbara M L C ; Zhang, Xiaohan ; Fonseca, Tatiana L ; Batistuzzo, Alice

AbstractThe Thr92Ala-Dio2 polymorphism is prevalent worldwide, with about 50% of the population carrying at least 1 allele. The Ala92-Dio2 allele encodes a less active type 2 deiodinase enzyme and has been associated with neurodegenerative diseases, hypertension, and insulin resistance. To understand why its phenotypic effects are variable across different populations, in this study we examined the impact of genetic background on the Thr92Ala-Dio2 polymorphism. We focused on the thyroid gland of 2 genetically distant mouse strains, the C57BL/6J (B6) and the FVB/N (FVB). While the B6-Ala92-Dio2 mice have no meaningful phenotype, the FVB-Ala92-Dio2 exhibit a goiter (about 2.3-fold heavier thyroid) with an about 1.7-fold enlarged thyroid follicular area and impaired hormonogenesis with reduced thyroglobulin content of T4 and T3, 35% to 50% lower serum T4, and about 3-fold elevated serum TSH levels. Notably, the FVB-Ala92-Dio2 thyroid glands showed transcriptional evidence of endoplasmic reticulum stress, unfolded protein response, autophagy, and apoptosis. Female FVB-Ala92-Dio2 mice exhibited a more pronounced thyroid phenotype than males. These findings underscore the critical role of genetic background in modulating the phenotype outcomes of the Thr92Ala-Dio2 polymorphism and highlight its potential implications for understanding variable disease susceptibility in human populations.

20 Mar 2025·Biological and Pharmaceutical Bulletin

Estradiol Regulates the Expression of Type 3 Deiodinase in a Chondrocyte Cell Line

Article

Author: Moriyama, Kenji ; Hayashi, Misa ; Hano, Hiromi ; Mitsutani, Mana ; Yamauchi, Ichiro ; Matsushita, Midori ; Tagami, Tetsuya ; Yokoyama, Mei

Although accelerated growth is observed in both sexes upon reaching puberty, the growth of girls ceases around menarche (the average age at menarche is 12-13 years in Japan). However, the molecular basis of the action of estrogen remains unclear. In this study, we investigated whether estrogen is involved in the differences in growth between males and females while focusing on thyroid hormone metabolic enzymes. We analyzed the promoters of iodothyronine deiodinase (DIO)2 and DIO3 by 17β-estradiol (E₂). ATDC5 cells (mouse chondrocytes cell line) were treated with E₂, and the expression of DIO2 and DIO3 mRNA and proteins was evaluated. Sham-operated (sham) or ovariectomized (OVX) female mice were treated daily with E₂ or vehicle for three consecutive weeks. Subsequently, the left femur was removed to evaluate the effect of E₂ on DIO2/DIO3 gene and protein expression. E₂ increased the transcriptional activity of DIO3 in a concentration-dependent manner. On the DIO3 promoter indicates the presence of an estrogen response element. DIO2 and DIO3 mRNA and protein expression in ATDC5 cells in the presence of E₂ was significantly increased, while DIO2 expression was unchanged. In vivo, we used OVX mice and E₂ supplementation as a model of amenorrhea for further investigation. DIO3 expression was significantly increased in mice treated with E₂ in OVX compared to that in mice treated with vehicle in sham. E₂ increases DIO3 expression in chondrocytes and long bone tissues, suggesting that E₂ may affect bone growth and cause sexual dimorphism during puberty.

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