Document Type
Article
Publication Date
4-26-2021
Abstract
Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
Recommended Citation
X. Zhang, A. P. Kellogg, C. E. Citterio, H. Zhang, D. Larkin, Y. Morishita, H. M. Targovnik, V. Balbi, and P. Arvan. Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death. JCI Insight. 2021;26(11):e148496. https://doi.org/10.1172/jci.insight.148496
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Animal Experimentation and Research Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Hormones, Hormone Substitutes, and Hormone Antagonists Commons, Other Pharmacy and Pharmaceutical Sciences Commons
Comments
This article was originally published in JCI Insight, volume 6, issue 11, in 2021. https://doi.org/10.1172/jci.insight.148496