Davies 2021 FASEB J
Davies KL, Smith DJ, El-Bacha T, Stewart ME, Easwaran A, Wooding PFP, Forhead AJ, Murray AJ, Fowden AL, Camm EJ (2021) Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner. FASEB J 35:21591. |
Davies Katie L, Smith Danielle J, El-Bacha Tatiana, Stewart Max E, Easwaran Akshay, Wooding Peter F P, Forhead Alison J, Murray Andrew J, Fowden Abigail L, Camm Emily J (2021) FASEB J
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 PGC1Ξ± (regulator of mitochondrial biogenesis) and thyroid hormone receptor Ξ² 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 prepartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism. β’ Keywords: Brain, Fetus, Mitochondria, Thyroid hormones β’ Bioblast editor: Reiswig R β’ O2k-Network Lab: UK Cambridge Murray AJ
Labels: MiParea: Respiration, mt-Biogenesis;mt-density
Organism: Other mammals
Tissue;cell: Nervous system
Preparation: Homogenate
Enzyme: Complex I, Complex II;succinate dehydrogenase
Coupling state: LEAK, OXPHOS Pathway: N, S, NS HRR: Oxygraph-2k
2021-08