Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has been previously implicated in clinically relevant massive cell death induced by toxins, anoxia, reactive oxygen species, and calcium overload. Here we show that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the natural PT pore present in intact mitochondria. The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2–like proteins. Although calcium, prooxidants, and several recombinant caspases (caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have lost their cytoprotective potential also lose their PT modulatory capacity. In conclusion, the PT pore complex may constitute a crossroad of apoptosis regulation by caspases and members of the Bcl-2 family.
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20 April 1998
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April 20 1998
The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins
Isabel Marzo,
Isabel Marzo
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Catherine Brenner,
Catherine Brenner
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Naoufal Zamzami,
Naoufal Zamzami
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Santos A. Susin,
Santos A. Susin
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Gisela Beutner,
Gisela Beutner
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Dieter Brdiczka,
Dieter Brdiczka
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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René Rémy,
René Rémy
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Zhi-Hua Xie,
Zhi-Hua Xie
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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John C. Reed,
John C. Reed
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Guido Kroemer
Guido Kroemer
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
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Isabel Marzo
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Catherine Brenner
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Naoufal Zamzami
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Santos A. Susin
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Gisela Beutner
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Dieter Brdiczka
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
René Rémy
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Zhi-Hua Xie
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
John C. Reed
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Guido Kroemer
From the *Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France; the ‡Faculty of Biology, University of Konstanz, D-78434 Konstanz, Germany; the §Centre National de la Recherche Scientifique, Université de Paris 11, F-91405 Orsay, France; and ‖The Burnham Institute, La Jolla, California 92037
Address correspondence to Guido Kroemer, 19 rue Guy Môquet, B.P. 8, F-94801 Villejuif, France. Phone: 33-1-49-58-35-13; Fax: 33-1-49-58-35-09; E-mail: [email protected]
1
Abbreviations used in this paper: Δψm, mitochondrial transmembrane potential; Ac-DEVD.cmk, acetyl-Asp-Glu-Val-Asp-chloromethylketone; A-YVAD.cmk, acetyl-Tyr-Val-Ala-Asp-chloromethylketone; AIF, apoptosis-inducing factor; ANT, adenine nucleotide translocator; Atr, atractyloside; diamide, diazenedicarboxylic acid bis 5N,N-dimethylamide; DiOC6(3), 3,3′dihexyloxacarbocyanine iodide; PT, permeability transition; PTPC, PT pore complex; RT, room temperature; VDAC, voltage-dependent anion channel; Z-VAD.fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone.
I. Marzo and C. Brenner contributed equally to this work.
Received:
October 22 1997
Revision Received:
January 13 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (8): 1261–1271.
Article history
Received:
October 22 1997
Revision Received:
January 13 1998
Citation
Isabel Marzo, Catherine Brenner, Naoufal Zamzami, Santos A. Susin, Gisela Beutner, Dieter Brdiczka, René Rémy, Zhi-Hua Xie, John C. Reed, Guido Kroemer; The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins . J Exp Med 20 April 1998; 187 (8): 1261–1271. doi: https://doi.org/10.1084/jem.187.8.1261
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