Hypothyroidism decreases the biogenesis in free mitochondria and neuronal oxygen consumption in the cerebral cortex of developing rats

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 C-13 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 T-3 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.This work was supported by Ministerio de Educaciín y Ciencia Grants SAF2004-06263-CO2-02 (to A.S.), SAF2004-06263-CO2-01, and SAF2007-62811 and Comunidad de Madrid Grant GR/SAL/0033/2004 (to A.P.-C.). Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas is funded by the Instituto de Salud Carlos III. T.B.R. is a recipient of a fellowship from the Fundaçâo para a Ciência e Tecnologia, Portugal (SFRH/BPD/26881/2006).Peer reviewe

The spot 14 protein inhibits growth and induces differentiation and cell death of human MCF-7 breast cancer cells

9 pages, 11 figures.The S14 (spot 14) gene encodes a protein that is predominantly expressed in lipogenic tissues, such as the liver, white and brown adipose tissues and the lactating mammary glands. Accumulated evidence suggests that S14 could play an important role in the induction of lipogenic enzymes. In humans, the S14 locus resides in the chromosome region 11q13, which is frequently amplified in breast tumours, and as a result, it has been suggested that this protein could play a role in the metabolism and growth of these kinds of tumours. In the present study, we have examined the effects of S14 overexpression in MCF-7 human breast cancer cells. We found that S14 causes (i) an inhibition of cell proliferation and of anchorage-independent growth, (ii) a marked reduction in the number of viable cells and (iii) the induction of differentiation and cell death of these cells. The inhibition of cell growth was associated with a decrease in the expression of cyclin D1 and a reduction of cyclin D1 promoter activity. Increased expression of S14 also caused the accumulation of cytochrome c in the cytosol and loss of mitochondrial membrane potential. These findings suggest that S14 may function as an important modulator of tumorigenesis in human breast by decreasing cell growth and inducing cell death and differentiation.This work was supported by the Dirección General de Enseñanza Superior e Investigación Científica through grants BMC2001-2342, SAF2004-06263-C02-01, and CAM GR/SAL/0033/2004 (to A.P. -C.) and grants PM99-0057, SAF2003-02962 and SAF2004-06263-C02-02 (to A.S.), and by the FIS (Fondo de Investigación Sanitaria) through grant 03C03/10 (to A.P. -C.). J. S.-R. is supported by the Agencia Española de Cooperación Internacional and by the research project 03C03/10.Peer reviewe

Hypothyroidism decreases the biogenesis in free mitochondria and neuronal oxygen consumption in the cerebral cortex of developing rats

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 13 C 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 T 3 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. (Endocrinology 150: 3953-3959, 2009) T hyroid hormones (T 4 , T 3 ) play an important role in mammalian tissue development and metabolism. Most of the actions of these hormones are mediated by the binding of T 3 to specific nuclear receptors that are ligand-dependent transcription factors that bind to thyroid hormone response elements in target genes and regulate transcription initiation (1, 2). These receptors belong to the nuclear receptor superfamily that is one of the largest families of transcription factors, which include, among others, the receptors for steroid hormones, retinoids, vitamin D 3 , peroxisomal proliferators, and many other transcription factors without known ligand (orphan receptors) (1). The activation of these receptors has been implicated in a broad range of cellular functions. The brain is an important target for thyroid hormone action, particularly during late development, as shown by numerous clinical and experimental data (3, 4). In the rat brain, the expression of thyroid hormone receptors increases rapidly after birth reaching the highest value by d 6 of postnatal life (5, 6). In agreement with this, during the perinatal period, the consequences of hypothyroidism are more dramatic and results in numerous alterations, such as reduction in dendritic arborization of cerebellar Purkinje cells; impairment of nerve process development; poor connectivity among neurons; changes in microtubule content; and impaired myelin deposition, cell migration, and synaptogenesis (4). The mitochondria are well-established targets of thyroid hormone action. The regulation by thyroid hormone of mitochondrial activity and biogenesis are extensively documented in numerous mammalian tissues such as liver, kidney, heart, and muscle (7). In these tissues the administration of T 3 increases oxygen consumption and oxidative phosphorylation, which underlies the calorigenic effect of this hormone. In the case of the brain, after initial contradictory reports (8 -11), it is now well established that the mitochondria are targets of thyroid hormon