Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Department of Internal Medicine, Division of Endocrinology and Metabolism, Gunma University Graduate School of Medicine, Maebashi, Japan.
Endocrinology. 2019 Sep 1;160(9):2085-2092. doi: 10.1210/en.2019-00312.
Autophagy is a catabolic process that involves the degradation of cellular components through the lysosomal machinery, relocating nutrients from unnecessary processes to more pivotal processes required for survival. It has been reported that systemic disruption of the Atg5 or Atg7 gene, a component of autophagy, is lethal and that its tissue-specific disruption causes tissue degeneration in several organs. However, the functional significance of autophagy in the thyroid glands remains unknown. Our preliminary data imply the possible involvement of dysfunctional autophagy in radiation-induced thyroid carcinogenesis. Therefore, we evaluated the effect of Atg5 gene knockout (KO) on thyroid morphology and function. To this end, Atg5flox/flox mice were crossed with TPO-Cre mice, yielding the thyroid follicular epithelial cell (thyrocyte)‒specific ATG5-deficient mice (Atg5thyr-KO/KO). Atg5 gene KO was confirmed by a lack of ATG5 expression, and disruption of autophagy was demonstrated by a decrease in microtubule-associated protein 1 light chain 3-II puncta and an increase in p62. Atg5thyr-KO/KO mice were born normally, and thyroid morphology, thyroid weights, and serum T4 and TSH levels were almost normal at 4 months. However, at 8 and 12 months, a decrease in the number of thyrocytes and an increase in TUNEL+-thyrocytes were observed in Atg5thyr-KO/KO mice even though thyroid function was still normal. The number of irregularly shaped (gourd-shaped) follicles was also increased. Excess oxidative stress was indicated by increased 8-hydroxy-2'-deoxyguanosine and 53BP1 foci in Atg5thyr-KO/KO mice. These data demonstrate that thyrocytes gradually undergo degradation/cell death in the absence of basal levels of autophagy, indicating that autophagy is critical for the quality control of thyrocytes.
自噬是一种分解代谢过程，涉及通过溶酶体机制降解细胞成分，将营养物质从不必要的过程转移到更关键的生存所需过程。据报道，自噬的一种组成部分 Atg5 或 Atg7 基因的系统破坏是致命的，其组织特异性破坏会导致几个器官的组织退化。然而，自噬在甲状腺中的功能意义尚不清楚。我们的初步数据表明，功能失调的自噬可能参与了放射性诱导的甲状腺癌发生。因此，我们评估了 Atg5 基因敲除 (KO) 对甲状腺形态和功能的影响。为此，Atg5flox/flox 小鼠与 TPO-Cre 小鼠交配，产生甲状腺滤泡上皮细胞 (thyrocyte) 特异性 ATG5 缺陷小鼠 (Atg5thyr-KO/KO)。通过缺乏 ATG5 表达证实了 Atg5 基因 KO，通过微管相关蛋白 1 轻链 3-II 斑点减少和 p62 增加证明了自噬的破坏。Atg5thyr-KO/KO 小鼠正常出生，甲状腺形态、甲状腺重量和血清 T4 和 TSH 水平在 4 个月时几乎正常。然而，在 8 个月和 12 个月时，即使甲状腺功能仍正常，Atg5thyr-KO/KO 小鼠的甲状腺细胞数量减少和 TUNEL+-thyrocytes 增加。不规则形状 (葫芦形) 滤泡的数量也增加了。Atg5thyr-KO/KO 小鼠中增加的 8-羟基-2'-脱氧鸟苷和 53BP1 焦点表明存在过多的氧化应激。这些数据表明，在没有基础水平自噬的情况下，甲状腺细胞逐渐经历降解/细胞死亡，表明自噬对甲状腺细胞的质量控制至关重要。
