Interaction of peroxidized cardiolipin with rat-heart mitochondrial membranes: induction of permeability transition and cytochrome c release.
Cardiolipin peroxidation plays a critical role in mitochondrial cytochrome c release and subsequent apoptotic process. Mitochondrial pore transition (MPT) is considered as an important step in this process. In this work, the effect of peroxidized cardiolipin on MPT induction and cytochrome c release in rat heart mitochondria was investigated. Treatment of mitochondria with micromolar concentrations of cardiolipin hydroperoxide (CLOOH) resulted in a dose-dependent matrix swelling, DeltaPsi collapse, release of preaccumulated Ca2+ and release of cytochrome c. All these events were inhibited by cyclosporin A and bongkrekic acid, indicating that peroxidized cardiolipin behaves as an inducer of MPT. Ca2+ accumulation by mitochondria was required for this effect. ANT (ADP/ATP translocator) appears to be involved in the CLOOH-dependent MPT induction, as suggested by the modulation by ligands and inhibitors of adenine nucleotide translocator (ANT). Together, these results indicate that peroxidized cardiolipin lowers the threshold of Ca2+ for MPT induction and cytochrome c release. This synergistic effect of Ca2+ and peroxidized cardiolipin on MPT induction and cytochrome c release in mitochondria, might be important in regulating the initial phase of apoptosis and also may have important implications in those physiopathological situations, characterized by both Ca2+ and peroxidized cardiolipin accumulation in mitochondria, such as aging, ischemia/reperfusion and other degenerative diseases.
Petrosillo
Giuseppe
G
Department of Biochemistry and Molecular Biology and Consiglio Nazionale delle Ricerche, Institute of Biomembranes and Bioenergetics, University of Bari, 70126 Bari, Italy.
Casanova
Giacoma
G
Matera
Mariagiuseppa
M
Ruggiero
Francesca Maria
FM
Paradies
Giuseppe
G
D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002308:Cardiolipins / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007511:Ischemia / Q000378:metabolism; D015227:Lipid Peroxidation; D008929:Mitochondria, Heart / Q000201:enzymology*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D051381:Rats
D002308:Cardiolipins; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D002118:Calcium