During apoptosis, an important pathway leading to caspase activation involves the release of cytochrome c from the intermembrane space of mitochondria. Using a cell-free system based on Xenopus egg extracts, we examined changes in the outer mitochondrial membrane accompanying cytochrome c efflux. The pro-apoptotic proteins, Bid and Bax, as well as factors present in Xenopus egg cytosol, each induced cytochrome c release when incubated with isolated mitochondria. These factors caused a permeabilization of the outer membrane that allowed the corelease of multiple intermembrane space proteins: cytochrome c, adenylate kinase and sulfite oxidase. The efflux process is thus nonspecific. None of the cytochrome c- releasing factors caused detectable mitochondrial swelling, arguing that matrix swelling is not required for outer membrane permeability in this system. Bid and Bax caused complete release of cytochrome c but only a limited permeabilization of the outer membrane, as measured by the accessibility of inner membrane-associated respiratory complexes III and IV to exogenously added cytochrome c . However, outer membrane permeability was strikingly increased by a macromolecular cytosolic factor, termed PEF (permeability enhancing factor). We hypothesize that PEF activity could help determine whether cells can recover from mitochondrial cytochrome c release. apoptosis Bid Bax cytochrome c mitochondrial outer membrane Footnotes Dr. Degli Esposti is on leave from the Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Vic 3169, Australia. . Abbreviations used in this paper: AK, adenylate kinase; FEISEM, field emission in-lens scanning electron microscopy; PEF, permeability enhancing factor; SOx, sulfite oxidase; tBid, truncated Bid; VDAC, voltage-dependent anion channel. Submitted: 5 August 1999 Revision requested 28 September 1999 Accepted: 12 October 1999
The Journal of Cell Biology – Rockefeller University Press
Published: Nov 15, 1999
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