CONICET | Buscador de Institutos y Recursos Humanos

Two decades ago, mitochondria were erecognized as a significant source of O2 active species. Superoxide anion (O2-) and its SOD-catalyzed product of dismutation, hydrogen peroxide (H2O2) are generated by auto-oxidation of ubisemiquinone and flavin radicals in the electron transfer chain. Recently, nitric oxide was reported as a physiologic compound able to markedly increase the mitochondrial formation of O2- and H2O2 consecutively to the inhibition of the electro transfer chain. Moreover, these effects could follow the activation of nitric oxide synthases specifically placed in inner mitochondrial membranes (mtNOS). Since free diffusible H2O2 could participate in redox signaling in the different stages of cell cycle, the aim of this work was to analyze modulatory changes in mtNOS in different conditions. In rat development, expression and activity of mtNOS were modulated in brain and liver. In brain, both mtNOS activity and expression increased by 5.6 fold from ambryonic E15 to postnatal P10, and afterwards decreased up to adult stage. In liver, mtNOS increased progressively from fetal life to P15. In both cases, changes in mtNOS were accompanied by parallel changes in Mn-SOD activity. In the two tissues, the L-Arg-dependent mitochondrial production rate and cytosolic steady-state concentrations of H2O2 followed closely the variations of mtNOS. Purified mitochondria obtained fron different mice mammary M3 and MM3 and lun P07 tumors expressed mtNOS but exhibited a remarkably low mtNOS activity which was 5.2±1 and 3.4±1 in mammary cells and 39.5±2 in adult liver. L-Arg-dependent H2O2 production was almost abolished in tumoral mitochondria. The results suggest that either low mtNOS in fetal development or, an impairment of mtNOS in tumors determine the lack of NO-dependent production of O2 active species which normally arrest cell cycle and conduct to the quiescent adult non-tumoral situation.

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