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J. Biol. Chem., Vol. 281, Issue 8, 4779-4786, February 24, 2006

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Hypothyroid Phenotype Is Contributed by Mitochondrial Complex I Inactivation Due to Translocated Neuronal Nitric-oxide Synthase^*

María C. Franco, Valeria G. Antico Arciuch, Jorge G. Peralta, Soledad Galli, Damián Levisman, Lidia M. López, Leonardo Romorini^¶, Juan J. Poderoso, and María C. Carreras^||1

From the Laboratory of Oxygen Metabolism, University Hospital, Instituto de Biología Celular y Neurociencia "Profesor Eduardo ^||de Robertis," Facultad de Medicina, ^¶Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, and Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, University of Buenos Aires, 1120-Buenos Aires, Argentina

Although transcriptional effects of thyroid hormones have substantial influence on oxidative metabolism, how thyroid sets basal metabolic rate remains obscure. Compartmental localization of nitric-oxide synthases is important for nitric oxide signaling. We therefore examined liver neuronal nitric-oxide synthase- (nNOS) subcellular distribution as a putative mechanism for thyroid effects on rat metabolic rate. At low 3,3',5-triiodo-L-thyronine levels, nNOS mRNA increased by 3-fold, protein expression by one-fold, and nNOS was selectively translocated to mitochondria without changes in other isoforms. In contrast, under thyroid hormone administration, mRNA level did not change and nNOS remained predominantly localized in cytosol. In hypothyroidism, nNOS translocation resulted in enhanced mitochondrial nitric-oxide synthase activity with low O₂ uptake. In this context, NO utilization increased active O₂ species and peroxynitrite yields and tyrosine nitration of complex I proteins that reduced complex activity. Hypothyroidism was also associated to high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase 1/2 and cyclin D1 levels. Similarly to thyroid hormones, but without changing thyroid status, nitric-oxide synthase inhibitor N-nitro-L-arginine methyl ester increased basal metabolic rate, prevented mitochondrial nitration and complex I derangement, and turned mitogen-activated protein kinase signaling and cyclin D1 expression back to control pattern. We surmise that nNOS spatial confinement in mitochondria is a significant downstream effector of thyroid hormone and hypothyroid phenotype.

Received for publication, November 9, 2005 , and in revised form, December 12, 2005.

^* This work was supported by research grants from the National Agency for Scientific and Technological Promotion (Pict 2000/08468), University of Buenos Aires (M063), National Research Council of Science and Technology, National Council of Scientific and Technical Investigation, and Fundación Perez Companc, Buenos Aires, Argentina. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Oxygen Metabolism, University Hospital, University of Buenos Aires, Córdoba 2351, 1120-Buenos Aires, Argentina. Tel./Fax: 54-11-5950-8811; E-mail: ccarreras{at}hospitaldeclinicas.uba.ar.

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