Cardiolipin oxidation is emerging as an important factor in
mitochondrial dysfunction as well as in the initial phase of the apoptotic process. We have previously shown that exogenously added peroxidized
cardiolipin sensitizes mitochondria to Ca(2+)-induced mitochondrial permeability transition (MPT) pore opening and promotes the release of
cytochrome c. In this work, the effects of intramitochondrial
cardiolipin peroxidation on Ca(2+)-induced MPT and on the
cytochrome c release from mitochondria were studied. The effects of
melatonin, a compound known to protect the mitochondria from oxidative damage, on both of these processes were also tested.
tert-Butylhydroperoxide (t-BuOOH), a
lipid-soluble
peroxide that promotes lipid peroxidation, was used to induce intramitochondrial
cardiolipin peroxidation. Exposure of heart mitochondria to t-BuOOH resulted in the oxidation of
cardiolipin, associated with an increased sensitivity of mitochondria to Ca(2+)-induced MPT and with the release of
cytochrome c from the mitochondria. All these processes were inhibited by micromolar concentrations of
melatonin. It is proposed that
melatonin inhibits
cardiolipin peroxidation in mitochondria, and this effect seems to be responsible for the protection afforded by this agent against the MPT induction and
cytochrome c release. Thus, manipulating the oxidation sensitivity of
cardiolipin with
melatonin may help to control MPT and
cytochrome c release, events associated with cell death, and thus, be used for treatment of those disorders characterized by mitochondrial
cardiolipin oxidation and Ca(2+) overload.