| Autor: |
Zhang X; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA., Kellogg AP; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA., Citterio CE; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA.; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo, Buenos Aires, Argentina., Zhang H; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA., Larkin D; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA., Morishita Y; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA.; Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan., Targovnik HM; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo, Buenos Aires, Argentina., Balbi VA; Department of Endocrinology and Growth, Hospital de Niños Sor María Ludovica, La Plata, Argentina., Arvan P; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA. |
| Abstrakt: |
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. |
