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 bi-allelic 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. We demonstrate that TGW2346R/ W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibit no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine is synthesized and brief treatment of TGrdw/rdw rats with anti-thyroid drug is lethal to the animals. When untreated, remarkably, thyroxine is synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they are iodinated and cannabilized by surrounding live thyrocytes. As long as the animals grow a goiter, circulating thyroxine increases. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provides the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
Xiaohan Zhang, Aaron P. Kellogg, Cintia E. Citterio, Hao Zhang, Dennis Larkin, Yoshiaki Morishita, Hector M. Targovnik, Viviana A. Balbi, Peter Arvan