Bid acts on the permeability transition pore complex to induce apoptosis.
Similar to most if not all pro-apoptotic members of the Bcl-2 family, Bid (and its truncated product t-Bid) triggers cell death via mitochondrial membrane permeabilization (MMP). This effect can be monitored in intact cells, upon microinjection of recombinant Bid protein into the cytoplasm, as well as in purified mitochondria, upon addition of Bid protein. Here we show that Bid-induced MMP can be inhibited, both in cells and in the cell-free system, by three pharmacological inhibitors of the permeability transition pore complex (PTPC), namely cyclosporin A, N-methyl-4-Val-cyclosporin A, and bongkrekic acid (a ligand of the adenine nucleotide translocase, ANT, one of the PTPC components). Bid effects on synthetic membranes were studied either in proteoliposomes or in synthetic bilayers subjected to electrophysiological measurements. Full length Bid preferentially permeabilizes membranes and induces the formation of large conductance channels at neutral pH, when added to liposomes or bilayers containing both purified ANT and Bax, yet has no or little effect combined with ANT or Bax alone. t-Bid acts on membranes containing ANT alone with the same efficiency as on those containing both ANT and Bax. These results suggest that the proapoptotic effects of Bid are mediated, at least in part, by its functional interaction with ANT, one of the major components of PTPC.
Zamzami
N
N
Centre National de la Recherche Scientifique, UMR 1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
El Hamel
C
C
Maisse
C
C
Brenner
C
C
Muñoz-Pinedo
C
C
Belzacq
A S
AS
Costantini
P
P
Vieira
H
H
Loeffler
M
M
Molle
G
G
Kroemer
G
G
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D001865:Bongkrekic Acid / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D003524:Cyclosporins / Q000494:pharmacology; D004553:Electric Conductivity; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability / Q000187:drug effects; D018272:Porins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D051023:BH3 Interacting Domain Death Agonist Protein; C494828:Bax protein, rat; C494816:Bid protein, rat; D002352:Carrier Proteins; D003524:Cyclosporins; D007473:Ion Channels; D008051:Lipid Bilayers; D008081:Liposomes; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018272:Porins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D001865:Bongkrekic Acid; D000226:Mitochondrial ADP, ATP Translocases