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Originally published In Press as doi:10.1074/jbc.M204580200 on August 28, 2002

J. Biol. Chem., Vol. 277, Issue 45, 42447-42455, November 8, 2002
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The Modulation of Mitochondrial Nitric-oxide Synthase Activity in Rat Brain Development*

Natalia A. RiobóDagger §, Mariana MelaniDagger §, Norberto Sanjuán, Mónica L. Fiszman||, María Clara Gravielle||, M. Cecilia CarrerasDagger , Enrique Cadenas**, and Juan J. PoderosoDagger Dagger Dagger

From the Dagger  Laboratory of Oxygen Metabolism, University Hospital, Av. Córdoba 2351, 1120 Buenos Aires, Argentina, the  Laboratory of Experimental Pathology, Department of Microbiology, School of Medicine, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina, || Instituto de Investigaciones Farmacológicas-CONICET, Juni'n 956, 1113 Buenos Aires, Argentina, and the ** Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90089-9121

Different mitochondrial nitric-oxide synthase (mtNOS) isoforms have been described in rat and mouse tissues, such as liver, thymus, skeletal muscle, and more recently, heart and brain. The modulation of these variants by thyroid status, hypoxia, or gene deficiency opens a broad spectrum of mtNOS-dependent tissue-specific functions. In this study, a new NOS variant is described in rat brain with an Mr of 144 kDa and mainly localized in the inner mitochondrial membrane. During rat brain maturation, the expression and activity of mtNOS were maximal at the late embryonic stages and early postnatal days followed by a decreased expression in the adult stage (100 ± 9 versus 19 ± 2 pmol of [3H]citrulline/min/mg of protein, respectively). This temporal pattern was opposite to that of the cytosolic 157-kDa nNOS protein. Mitochondrial redox changes followed the variations in mtNOS activity: mtNOS-dependent production of hydrogen peroxide was maximal in newborns and decreased markedly in the adult stage, thus reflecting the production and utilization of mitochondrial matrix nitric oxide. Moreover, the activity of brain Mn-superoxide dismutase followed a developmental pattern similar to that of mtNOS. Cerebellar granular cells isolated from newborn rats and with high mtNOS activity exhibited maximal proliferation rates, which were decreased by modifying the levels of either hydrogen peroxide or nitric oxide. Altogether, these findings support the notion that a coordinated modulation of mtNOS and Mn-superoxide dismutase contributes to establish the rat brain redox status and participate in the normal physiology of brain development.


* This work was supported by research grants from the University of Buenos Aires (Grants TM047 and M026), the National Agency for Promotion of Scientific and Technological Development (Grant PICT 02372), the Fundación Perez Companc, Buenos Aires, Argentina, and the National Institutes of Health (Grant 1 RO1 AG 16718).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

Dagger Dagger To whom correspondence should be addressed. E-mail: jpoderos@fmed.uba.ar.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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