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Hypothyroidism Decreases the Biogenesis in Free Mitochondria and Neuronal Oxygen Consumption in the Cerebral Cortex of Developing Rats

Departamentos de Bioquímica y Biología Molecular (B.M., E.G., J.P.K., A.S.) y Biología Celular (E.G.), Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; Instituto de Investigaciones Biomédicas (T.B.R., A.P.-C.), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain; and Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (A.P.-C.)

Address all correspondence and requests for reprints to: A. Santos, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense 28040 Madrid, Spain. E-mail: piedras3{at}med.ucm.es; or A. Perez-Castillo, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: aperez{at}iib.uam.es.

Thyroid hormone plays a critical role in mitochondrial biogenesis in two areas of the developing brain, the cerebral cortex and the striatum. Here we analyzed, in the cerebral cortex of neonatal rats, the effect of hypothyroidism on the biogenesis in free and synaptosomal mitochondria by analyzing, in isolated mitochondria, the activity of respiratory complex I, oxidative phosphorylation, oxygen consumption, and the expression of mitochondrial genome. In addition, we studied the effect of thyroid hormone in oxygen consumption in vivo by determining metabolic flow through ¹³C nuclear magnetic resonance spectroscopy. Our results clearly show that in vivo, hypothyroidism markedly reduces oxygen consumption in the neural population of the cerebral cortex. This effect correlates with decreased free mitochondria biogenesis. In contrast, no effect was observed in the biogenesis in synaptosomal mitochondria. The parameters analyzed were markedly improved after T₃ administration. These results suggest that a reduced biogenesis and the subsequent reduction of respiratory capacity in free mitochondria could be the underlying cause of decreased oxygen consumption in the neurons of the cerebral cortex of hypothyroid neonates.