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  • Original Paper
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Bid acts on the permeability transition pore complex to induce apoptosis

Abstract

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 transiton 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.

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Abbreviations

AIF:

apoptosis-inducing factor

ANT:

adenine nucleotide translocator

Atr:

atractyloside

BA:

bongkrekic acid

CsA:

cyclosporin A

Cyt-c:

cytochrome c

mod. CsA:

N-methyl-4-Val-cyclosporin A

IM:

inner membrane

MMP:

mitochondrial membrane permeabilization

4-MU:

4-methylumbelliferone

4-MUP:

4-methylumbelliferylphosphate

OM:

outer membrane

PTPC:

permeability transition pore complex

PA:

König's polyanion

t-Bid:

truncated Bid

VDAC:

voltage dependent anion channel

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Acknowledgements

We thank Drs J-C Martinou and B Antonsson (Serono, Geneva, Switzerland) for the generous gift of recombinant Bid, tBid, and Bax, as well as HK Lorenzo for helpful discussion. This work has been supported by a special grant from the Ligue Nationale contre le Cancer as well as grants from ANRS, FRM, and the European Commission (to GKroemer). C El Hamel receives a grant from the Ligue Départmental contre le Cancer, Val-de-Marne, A-S Belzacq from ARC, M Loeffler from the Austrian Science Foundation, and P Costantini from FRM.

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Zamzami, N., Hamel, C., Maisse, C. et al. Bid acts on the permeability transition pore complex to induce apoptosis. Oncogene 19, 6342–6350 (2000). https://doi.org/10.1038/sj.onc.1204030

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