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J. Biol. Chem., Vol. 277, Issue 45, 42447-42455, November 8, 2002
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From the 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.
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, Jun
'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

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