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Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner.
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.
Afiliação
  • Davies KL; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Smith DJ; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • El-Bacha T; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Stewart ME; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Easwaran A; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Wooding PFP; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Forhead AJ; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Murray AJ; Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK.
  • Fowden AL; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Camm EJ; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
FASEB J ; 35(5): e21591, 2021 05.
Article em En | MEDLINE | ID: mdl-33891344
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 ß 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosforilação Oxidativa / Efeitos Tardios da Exposição Pré-Natal / Hormônios Tireóideos / Regulação da Expressão Gênica / Doenças Mitocondriais / Hipotireoidismo / Mitocôndrias Tipo de estudo: Etiology_studies Limite: Animals / Pregnancy Idioma: En Revista: FASEB J Assunto da revista: BIOLOGIA / FISIOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosforilação Oxidativa / Efeitos Tardios da Exposição Pré-Natal / Hormônios Tireóideos / Regulação da Expressão Gênica / Doenças Mitocondriais / Hipotireoidismo / Mitocôndrias Tipo de estudo: Etiology_studies Limite: Animals / Pregnancy Idioma: En Revista: FASEB J Assunto da revista: BIOLOGIA / FISIOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Reino Unido