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© The Rockefeller University Press, 0021-9525/1999//809 $5.00
The Journal of Cell Biology, Volume 147, Number 4, , 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. Klucka, Mauro Degli Espostie, Guy Perkinsb, Christian Renkenc, Tomomi Kuwanaa, Ella Bossy-Wetzela, Martin Goldbergd, Terry Allend, Michael J. Barbere, Douglas R. Greena, and Donald D. Newmeyera

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
Division of Cellular Immunology, La Jolla Institute of Allergy/Immunology, 10355 Science Center Drive, San Diego, CA 92121.(858) 558-3526(858) 558-3539

don_newmeyer{at}liai.org

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.

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

© 1999 The Rockefeller University Press

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.


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J. Cell Biol. 1999 147: 1-2. [Full Text] [PDF]





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