Reactivity of mitochondrial peroxiredoxins with biological hydroperoxides

Mitochondria are main sources of biological hydroperoxides, including hydrogen peroxide, peroxynitrite and various organic hydroperoxides. Most of these species are involved in the regulation of cellular functions when formed at low, physiological levels. Additionally, they can cause oxidative damage when formed at higher rates, eventually leading to mitochondrial disfunction and cytotoxicity. Different peroxidases sense the levels and catalyze the reduction of mitochondrial hydroperoxides. Among them, peroxiredoxin 3 and peroxiredoxin 5 decompose most hydrogen peroxide, peroxynitrite and free fatty acid hydroperoxides formed in the mitochondrial matrix. Kinetic considerations indicate that the role of selenol-dependent glutathione peroxidases in the reduction of these soluble hydroperoxides in mitochondria would be secondary. Glutathione peroxidase 4, which has a unique phospholipid hydroperoxide peroxidase activity, is only expressed in the mitochondria of selected tissues. Peroxiredoxin 3 catalyzes the reduction of hydroperoxides, but is also hyperoxidized and inactivated by them, in particular by free fatty acid hydroperoxides which react at high rate constants. Indeed, computer-assisted simulations support that free fatty acid hydroperoxides significantly contribute to Prdx3 hyperoxidation under biologically-relevant conditions. In addition, kinetic data indicate that hydroperoxides may partially diffuse to the cytosol. Several open questions regarding the oxidizing substrate specificities of mitochondrial peroxiredoxins and their modulation by CO₂ are presented. Thus, peroxiredoxins 3 and 5 are the main sensors of mitochondrial hydroperoxides, provide protection from their excess and also determine the ability of these reactive species to diffuse through mitochondria; these combined actions of the mitochondrial peroxiredoxins impact redox regulation and outcomes of physiological or pathological processes.