The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins.
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.
Marzo
I
I
Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, F-94801 Villejuif, France.
Brenner
C
C
Zamzami
N
N
Susin
S A
SA
Beutner
G
G
Brdiczka
D
D
Rémy
R
R
Xie
Z H
ZH
Reed
J C
JC
Kroemer
G
G
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D008081:Liposomes; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D008081:Liposomes; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003546:Cysteine Endopeptidases