LIPID-PEROXIDATION IN MITOCHONDRIAL INNER MEMBRANES .1. AN INTEGRATIVE KINETIC-MODEL

An integrative mathematical model was developed to obtain an overall p icture of lipid hydroperoxide metabolism in the mitochondrial inner me mbrane and surrounding matrix environment. The model explicitly consid ers an aqueous and a membrane phase, integrates a wide set of experime ntal data, and unsupported assumptions were minimized. The following b iochemical processes were considered: the classic reactional scheme of lipid peroxidation; antioxidant and pro-oxidant effects of vitamin E; pro-oxidant effects of iron; action of phospholipase A(2), glutathion e-dependent peroxidases, glutathione reductase and superoxide dismutas e; production of superoxide radicals by the mitochondrial respiratory chain; oxidative damage to proteins and DNA. Steady-state fluxes and c oncentrations as well as half-lives and mean displacements for the mai n metabolites were calculated. A picture of lipid hydroperoxide physio logical metabolism in mitochondria in vivo showing the main pathways i s presented. The main results are: (a) perhydroxyl radical is the main initiation agent of Lipid peroxidation (with a flux of 10(-7)Ms(-1)); (b) vitamin E efficiently inhibits lipid peroxidation keeping the amp lification (kinetic chain length) of lipid peroxidation at low values (congruent to 10); (c) only a very minor fraction of lipid hydroperoxi des escapes reduction via glutathione-dependent peroxidases; (d) oxidi zed glutathione is produced mainly from the reduction of hydrogen pero xide and not from the reduction of lipid hydroperoxides. Copyright (C) 1996 Elsevier Science Inc.