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Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator

Oncogene volume 19, pages 329–336 (2000)Cite this article

Abstract

Bcl-2 family protein including anti-apoptotic (Bcl-2) or pro-apoptotic (Bax) members can form ion channels when incorporated into synthetic lipid bilayers. This contrasts with the observation that Bcl-2 stabilizes the mitochondrial membrane barrier function and inhibits the permeability transition pore complex (PTPC). Here we provide experimental data which may explain this apparent paradox. Bax and adenine nucleotide translocator (ANT), the most abundant inner mitochondrial membrane protein, can interact in artificial lipid bilayers to yield an efficient composite channel whose electrophysiological properties differ quantitatively and qualitatively from the channels formed by Bax or ANT alone. The formation of this composite channel can be observed in conditions in which Bax protein alone has no detectable channel activity. Cooperative channel formation by Bax and ANT is stimulated by the ANT ligand atractyloside (Atr) but inhibited by ATP, indicating that it depends on the conformation of ANT. In contrast to the combination of Bax and ANT, ANT does not form active channels when incorporated into membranes with Bcl-2. Rather, ANT and Bcl-2 exhibit mutual inhibition of channel formation. Bcl-2 prevents channel formation by Atr-treated ANT and neutralizes the cooperation between Bax and ANT. Our data are compatible with a ménage à trois model of mitochondrial apoptosis regulation in which ANT, the likely pore forming protein within the PTPC, interacts with Bax or Bcl-2 which influence its pore forming potential in opposing manners.

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Abbreviations

ANT:

adenine nucleotide translocator

Atr:

atractyloside

ΔΨm:

mitochondrial transmembrane potential

PT:

permeability transition

PTPC:

permeability transition pore complex

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Acknowledgements

We are indebted to Dr Pat Schmid (The Hormel Institute, University of Minnesota, USA) and Professor Paolo Bernardi (University of Padova, Padova, Italy) for antisera. This work has been supported by grants from ANRS, ARC, FRM, INSERM, LNC, and the French Ministry for Science (to G Kroemer), GDR no. 790 (to H Duclohier), NIH grant AG 15393 (to JC Reed) and Région Haute Normandie (Ph.D. grant to H Cadiou). HLA Vieira receives a fellowship from the Fundação para a Ciência e a Tecnolgia PRAXIS XXI, Portugal.

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Authors and Affiliations

  1. Centre National de la Recherche Scientifique, UPR420, 19 rue Guy Môquet, Villejuif, F-94801, France

    Catherine Brenner, Helena LA Vieira, Naoufal Zamzami, Isabel Marzo & Guido Kroemer

  2. Centre National de la Recherche Scientifique, UPRES-A6022, Universitè Technologique de Compiègne, Compiègne, F-60205, France

    Catherine Brenner

  3. Centre National de la Recherche Scientifique, UMR6522, Université de Rouen (IFRMP 23), Mont St. Aignan, F-76821, France

    Hervé Cadiou & Hervé Duclohier

  4. The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, 92037, California, CA, USA

    Zhihua Xie & John C Reed

  5. McMaster University Medical Centre, 1200 Main Street West, Hamilton, L8N 3Z5, Ontario, Canada

    Brian Leber

  6. Department of Biochemistry, McMaster University, 1200 Main Street West, Hamilton, L8N 3Z5, Ontario, Canada

    David Andrews

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Brenner, C., Cadiou, H., Vieira, H. et al. Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene 19, 329–336 (2000). https://doi.org/10.1038/sj.onc.1203298

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