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 142days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105dGA (term ~145dGA). 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 128dGA and 142dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor β at 128dGA and 142dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128dGA and 142dGA, 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.
Highlights
Congenital hypothyroidism affects 1 in 2000 neonates worldwide.[1]
More recent studies have shown that thyroid hormones are involved in the normal perinatal maturation of mitochondrial oxidative phosphorylation (OXPHOS) capacity in metabolic tissues including liver, skeletal muscle, and adipocytes.12-14 relatively little is known about the role of thyroid hormones in cerebral mitochondrial development,[15] despite the high energy demands associated with the increased neuronal differentiation and activity during the perinatal period.[16]
This study examined mitochondrial function of the cortex and cerebellum of thyroidectomized fetal sheep during late gestation in relation to expression of genes and proteins involved in mitochondrial biogenesis, electron transport, and OXPHOS efficiency
Summary
Congenital hypothyroidism affects 1 in 2000 neonates worldwide.[1]. It is associated with prolonged gestation, abnormal birth weight, and impaired neurological development.1-3 Even with postnatal hormone therapy, these infants are at greater risk of cognitive delay, lower intelligence, and deficits in fine motor control in later childhood.[2,4] neonatal subclinical hypothyroidism is associated with delayed attainment of the normal neurodevelopmental and educational milestones.[4,5] Recent studies have indicated that the effects of fetal hypothyroidism on human brain development may extend beyond the psychomotor to include central regulation of metabolism in later life.[5]. Thyroid hormones stimulate tissue accretion and differentiation in utero, and have a key role in maturation of tissues essential for immediate neonatal survival, such as the lungs and liver.[6] Perinatal hypothyroidism adversely affects neuronal development of specific brain regions in newborn rodents and sheep.[2,7] In adulthood, thyroid hormones have a central role in controlling thermogenesis and metabolic rate, in part, through actions on mitochondrial oxidative phosphorylation (OXPHOS).[8] At birth, energy demands increase for new postnatal processes, such as thermogenesis, muscular activity, and metabolic homeostasis, in association with a rise in oxygen consumption.[6,9] Hypothyroidism is known to limit this rise in oxygen consumption and impair thermogenesis in newborn lambs.[10,11] More recent studies have shown that thyroid hormones are involved in the normal perinatal maturation of mitochondrial OXPHOS capacity in metabolic tissues including liver, skeletal muscle, and adipocytes.12-14 relatively little is known about the role of thyroid hormones in cerebral mitochondrial development,[15] despite the high energy demands associated with the increased neuronal differentiation and activity during the perinatal period.[16]. Sheep were chosen for this study because of their similarity to human infants in terms of the autonomy of the fetal hypothalamic-p ituitary-thyroid axis in late gestation and of the timing of key developmental events in the brain compared to more altricial rodent species.[6,7] The study tested the hypothesis that thyroid hormone deficiency would impair mitochondrial OXPHOS of the brain before birth, in association with altered cerebral morphology
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