
<ArticleTitle><prot>Mitochondrial <prot>cytochrome c</prot></prot> release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin B-induced apoptosis.</ArticleTitle>
<AbstractText>Permeability transition, and a subsequent drop in mitochondrial membrane potential (DeltaPsi(m)), have been suggested to be mechanisms by which <prot>cytochrome c</prot> is released from the mitochondria into the cytosol during apoptosis. Furthermore, a drop in DeltaPsi(m) has been suggested to be an obligate early step in the apoptotic pathway. Didemnin B, a branched cyclic peptolide described to have immunosuppressive, anti-tumour, and anti-viral properties, induces rapid apoptosis in a range of mammalian cell lines. Induction of apoptosis by didemnin B in cultured human pro-myeloid HL-60 cells is the fastest and most complete ever described with all cells being apoptotic after 3 h of treatment. By utilizing the system of didemnin B-induced apoptosis in HL-60 cells, and the potent inhibitors of mitochondrial permeability transition, cyclosporin A and bongkrekic acid, we show that permeability transition as determined by changes in DeltaPsi(m) and mitochondrial Ca2+ fluxing, is not a requirement for apoptosis or <prot>cytochrome c</prot> release. In this system, changes in mitochondrial membrane potential and <prot>cytochrome c</prot> release are shown to be dependent on caspase activation, and to occur concurrently with the release of <prot>caspase-9</prot> from mitochondria, genomic DNA fragmentation and apoptotic body formation.</AbstractText>
