Mitochondrial peroxynitrite generation is mainly driven by superoxide steady-state concentration rather than by nitric oxide steady-state concentration

Abstract

In biological systems, ONOO- production depends on production rates of NO and O2-, and on the reactions of these two free radicals with other biological components, which limit the local concentrations of NO and O2-. In mitochondria, O2- is generated through the autoxidation of semiquinones at Complexes I and III, and it may suffer the SOD-catalysed dismutation reaction to produce H2O2 or react with NO in a classical termination reaction between free radicals. These diffusion-controlled reactions kinetically compete for O2- degradation. Results from our laboratory have shown that even in physiopathological situations in which NO production is reduced, such as the mitochondrial dysfunction associated to stunned heart, mitochondrial ONOO- production rate may be slightly increased if the steady-state concentration of O2- is augmented. The enhancement in O2- concentration leads to an increase in its degradation by reaction with NO, decreasing NO bioavailability and increasing ONOO- production rate. Therefore, mitochondrial ONOO- generation is mainly driven by O2- rather than by NO steady-state concentrations. In this scenario, the switch from signalling pathways of NO to oxidative damage takes place and oxidation reactions of biomolecules or modification of proteins by nitration may occur.