Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin b-induced apoptosis

David R. Grubb, Jennifer D. Ly, François Vaillant, Karina L. Johnson, Alfons Lawen

Research output: Contribution to journalArticleResearchpeer-review

38 Citations (Scopus)


Permeability transition, and a subsequent drop in mitochondrial membrane potential (Δψm), have been suggested to be mechanisms by which cytochrome c is released from the mitochondria into the cytosol during apoptosis. Furthermore, a drop in Δψm 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 Δψm and mitochondrial Ca2+ fluxing, is not a requirement for apoptosis or cytochrome c release. In this system, changes in mitochondrial membrane potential and cytochrome c release are shown to be dependent on caspase activation, and to occur concurrently with the release of caspase-9 from mitochondria, genomic DNA fragmentation and apoptotic body formation.

Original languageEnglish
Pages (from-to)4085-4094
Number of pages10
Issue number30
Publication statusPublished - 5 Jul 2001


  • Apoptosis
  • Caspases
  • Cytochrome c
  • Didemnin b
  • Mitochondria
  • Permeability transition

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