出生前甲状腺激素缺乏会以区域特异性方式损害脑线粒体呼吸功能的发育

Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before

birth in a region-specific manner

Keywords：Brain, Fetus, Mitochondria, Thyroid hormones

关键词：大脑、胎儿、线粒体、甲状腺激素

哺乳动物：其他哺乳动物
作者：Davies KL, Smith DJ, El-Bacha T, Stewart ME, Easwaran A, Wooding PFP, Forhead AJ, Murray AJ, Fowden AL, Camm EJ
出版期刊：《FASEB Journal 》（2021/4/23）

Abstract：

Thyroid hormones regulate adult metabolism partly through actions on mitochondrial oxidative phosphorylation (OXPHOS). They also affect neurological development of the brain, but their role in cerebral OXPHOS before birth remains largely unknown, despite the increase in cerebral energy demand during the neonatal period. Thus, this study examined prepartum development of cerebral OXPHOS in hypothyroid fetal sheep. Using respirometry, Complex I (CI), Complex II (CII), and combined CI&CII OXPHOS capacity were measured in the fetal cerebellum and cortex at 128  and 142  days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105 dGA (term ~145 dGA). Mitochondrial electron transfer system (ETS) complexes, mRNA transcripts related to mitochondrial biogenesis and ATP production, and mitochondrial density were quantified using molecular techniques. Cerebral morphology was assessed by immunohistochemistry and stereology. In the cortex, hypothyroidism reduced CI-linked respiration and CI abundance at 128  dGA and 142 dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor β at 128 dGA and 142 dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128 dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128 dGA and 142 dGA, respectively. These alterations in mitochondrial function were accompanied by reduced myelination. The findings demonstrate the importance of thyroid hormones in the repartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism.

文章摘要：

甲状腺激素部分通过对线粒体氧化磷酸化 (OXPHOS) 的作用来调节成人代谢。它们也影响大脑的神经发育，但尽管新生儿期脑能量需求增加，但它们在出生前在脑 OXPHOS 中的作用仍然很大程度上未知。因此，本研究检查了甲状腺功能减退的胎羊中脑 OXPHOS 的产前发育。使用O2k，在 105 dGA 手术甲状腺切除术或假手术后，测量胎龄 128 天和 142 天 (dGA)的胎儿中的小脑和皮质中的复合物 I (CI)、复合物 II (CII) 和联合 CI&CII OXPHOS 能力（术语约 145 dGA）。使用分子技术对线粒体电子转移系统 (ETS) 复合物、与线粒体生物发生和 ATP 产生相关的 mRNA 转录物以及线粒体密度进行量化。通过免疫组织化学和体视学评估大脑形态。在皮质中，甲状腺功能减退分别在 128 dGA 和 142 dGA 降低 CI 相关呼吸和 CI 丰度，并分别在 128 dGA 和 142 dGA 引起 PGC1α（线粒体生物发生调节剂）和甲状腺激素受体 β 的上调。相比之下，在小脑中，甲状腺功能减退在 128 dGA 时减少了 CI&II 和 CII 相关的呼吸，对 ETS 复合物没有显着影响。此外，小脑糖皮质激素受体和腺嘌呤核苷酸转位酶 (ANT1) 分别在 128 dGA 和 142 dGA 下调。线粒体功能的这些改变伴随着髓鞘形成的减少。研究结果证明了甲状腺激素在脑线粒体恢复成熟中的重要性，并对与人类早产和先天性甲状腺功能减退症相关的神经发育异常的病因和治疗具有重要意义。

点击链接即可查看和下载文章：https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202100075R

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