Ascorbate and low concentrations of FeSO4 induce the Ca2+-dependent pore in rat liver mitochondria

Oxidative stress is one of the most frequent causes of tissue and cell inju ry in various pathologies. The molecular mechanism of mitochondrial damage under conditions of oxidative stress induced in vitro with low concentratio ns of FeSO4 and ascorbate (vitamin C) was studied. FeSO4 (1-4 muM) added to rat liver mitochondria that were incubated in the presence of 2.3 mM ascor bate induced (with a certain delay) a decrease in membrane potential and hi gh-amplitude swelling. It also significantly decreased the ability of mitoc hondria to accumulate exogenous Ca2+. All the effects of FeSO4 + ascorbate were essentially prevented by cyclosporin A, a specific inhibitor of the mi tochondrial Ca2+-dependent pore (also known as the mitochondrial permeabili ty transition). EGTA restored the membrane potential of mitochondria de-ene rgized with FeSO4 + ascorbate. We hypothesize that oxidative stress induced in vitro with FeSO4 and millimolar concentrations of ascorbate damages mit ochondria by inducing the cyclosporin A-sensitive Ca2+-dependent pore in th e inner mitochondrial membrane.