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 auto oxidation of semiquinones at Complexes I and III, and it may suffer the SODcatalyzed dismutation reaction to produce H2 O2 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 ONOOgeneration is mainly driven by O2 - rather than by NO steady-state concentrations. In this scenario, the switch from NO-signaling pathways to oxidative damage takes place. The modification of crucial biomolecules by nitration or oxidation can lead to the bioenergetics failure that underlies physiopathological conditions such as neurodegenerative diseases, ischemia-reperfusion, Diabetes, endotoxic shock and aging.