The Pro-apoptotic Proteins, Bid and Bax, Cause a Limited Permeabilization of the Mitochondrial Outer Membrane that Is Enhanced by Cytosol

doi:10.1083/jcb.147.4.809

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© The Rockefeller University Press, 0021-9525/1999/11/809/ $5.00
The Journal of Cell Biology, Volume 147, Number 4, November 15, 1999 809-822

Original Article

The Pro-apoptotic Proteins, Bid and Bax, Cause a Limited Permeabilization of the Mitochondrial Outer Membrane that Is Enhanced by Cytosol

Ruth M. Kluck^a, Mauro Degli Esposti^e, Guy Perkins^b, Christian Renken^c, Tomomi Kuwana^a, Ella Bossy-Wetzel^a, Martin Goldberg^d, Terry Allen^d, Michael J. Barber^e, Douglas R. Green^a, and Donald D. Newmeyer^a
^a Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121
^b Department of Neurosciences, University of California San Diego, San Diego, California 92093
^c Biology Department, San Diego State University, San Diego, California 92182
^d Paterson Institute, Christie Hospital NHS Trust, Manchester M20 9BX, United Kingdom
^e Department of Biochemistry and Molecular Biology, University of South Florida, College of Medicine, Tampa, Florida 33612

Correspondence to: Donald D. Newmeyer, Division of Cellular Immunology, La Jolla Institute of Allergy/Immunology, 10355 Science Center Drive, San Diego, CA 92121. Tel:(858) 558-3539 Fax:(858) 558-3526 E-mail:don_newmeyer{at}liai.org.

During apoptosis, an important pathway leading to caspase activationinvolves the release of cytochrome c from the intermembranespace of mitochondria. Using a cell-free system based on Xenopusegg extracts, we examined changes in the outer mitochondrialmembrane accompanying cytochrome c efflux. The pro-apoptoticproteins, Bid and Bax, as well as factors present in Xenopusegg cytosol, each induced cytochrome c release when incubatedwith isolated mitochondria. These factors caused a permeabilizationof the outer membrane that allowed the corelease of multipleintermembrane space proteins: cytochrome c, adenylate kinaseand sulfite oxidase. The efflux process is thus nonspecific.None of the cytochrome c-releasing factors caused detectablemitochondrial swelling, arguing that matrix swelling is notrequired for outer membrane permeability in this system. Bidand Bax caused complete release of cytochrome c but only a limitedpermeabilization of the outer membrane, as measured by the accessibilityof inner membrane-associated respiratory complexes III and IVto exogenously added cytochrome c. However, outer membrane permeabilitywas strikingly increased by a macromolecular cytosolic factor,termed PEF (permeability enhancing factor). We hypothesize thatPEF activity could help determine whether cells can recoverfrom mitochondrial cytochrome c release.

Key Words: apoptosis, Bid, Bax, cytochrome c, mitochondrial outer membrane

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