oxidants and antioxidants in biology - Oxygen Club of California

Mitochondrial nitric oxide synthase and redox signaling
M.C. CARRERAS, P. FINOCCHIETTO, D. CONVERSO, M. LABATO,
M.C. FRANCO, S. GALLI, AND J.J. PODEROSO
Laboratory of Oxygen Metabolism, University of Buenos Aires, Buenos Aires,
Argentina
It is noteworthy that changes in the expression and activity of
constitutive mtNOS will be followed by significant variations in
matrix NO steady-state levels in the relatively small and welldifferentiated
mitochondrial compartment (Giulivi et al, 1998). The
mitochondrial utilization of NO involves the production of superoxide
anion and hydrogen peroxide (H 2 O 2 ) a species freely diffusible
outside the mitochondria (Poderoso et al, 1996 and 1999, Antunez
and Cadenas, 2000). In the last years, cumulative evidence
showed that H 2 O 2 production and the consequent oxidative stress
level play an important role in the activation of signaling molecules
which control the complex machinery involved in cell proliferation,
differentiation, apoptosis, senescence, cell transformation and cancer
(Davies 2000, Huang et al, 2000). On this basis, it was interesting
to analyze the modulation of mtNOS in the frame of cellular
redox state and cell cycle progression. These variables were then
followed in normal quiescent tissues, in proliferating ones, in tumoral
tissues and in transformed cell lines. Collectively, the data
show that a) normal proliferating tissues like developing brain or
liver have substantially less mtNOS content and mitochondrial
H 2 O 2 yield than quiescent non-proliferating tissues b) transition of
proliferation to tissue differentiation involves a relatively rapid
mtNOS increase. Conversely, liver proliferation induced by a single
T4 dose is followed by a marked and transient decrease of
mtNOS. In addition, tumoral cells exhibit very low mtNOS activity
and H 2 O 2 . Therefore, cascades like D cyclins and MAPKs responding
to H 2 O 2 result ultimately modulated by changes in
mtNOS, which may constitute a platform contributing to persistent
cell proliferation or to cell cycle arrest.
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