The modulation of mitochondrial nitric-oxide synthase activity in rat brain development.
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 M(r) 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 [(3)H]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.
Natalia A
NA
Riobo
Mariana
M
Melani
Norberto
N
Sanjuan
Monica L
ML
Fiszman
Maria Clara
MC
Gravielle
M Cecilia
MC
Carreras
Enrique
E
Cadenas
Juan J
JJ
Poderoso
D000375:Aging; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000254:growth & development*; D002118:Calcium / Q000494:pharmacology; D002458:Cell Fractionation; D005314:Embryonic and Fetal Development; D005486:Flavin Mononucleotide / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D014644:Genetic Variation; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D013367:Submitochondrial Particles / Q000201:enzymology
D005182:Flavin-Adenine Dinucleotide; D005486:Flavin Mononucleotide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D002118:Calcium