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Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim

Oncogene volume 21, pages 4944–4956 (2002)Cite this article

Abstract

Bcl-2 family of proteins regulates apoptosis by controlling mitochondrial membrane permeability. We have previously shown that the voltage-dependent anion channel (VDAC) plays a crucial role in apoptotic changes of the mitochondria and its activity is directly regulated by some Bcl-2 family members, including Bcl-2/Bcl-xL and Bax/Bak but not Bid. Here, we showed that in isolated mitochondria, Bim induced loss of membrane potential and cytochrome c release like Bax/Bak, with these changes being inhibited by an anti-VDAC antibody. In addition, microinjection of the anti-VDAC antibody significantly reduced Bim-induced apoptosis. Study using purified proteins indicated that Bim directly interacts with the VDAC. Immunoprecipitation analysis revealed that Bim interacts with the VDAC and the interaction is remarkably enhanced during apoptosis. An experiment using liposomes indicated that Bim enhanced VDAC activity, as did Bax/Bak. Furthermore, Bim (but not tBid) was able to induce apoptotic changes of yeast mitochondria in a VDAC-dependent manner, and also induced the lysis of red blood cells, with this effect being inhibited by the anti-VDAC antibody. These results indicate that Bim has an ability to activate directly the VDAC, which plays an important role in apoptosis of mammalian cells.

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Abbreviations

BH:

Bcl-2 homology

BK:

bongkrekic acid

CsA:

cyclosporin A

cyt. c:

cytochrome c

Δψ:

mitochondrial membrane potential

NRI:

normal rabbit IgG

PT:

permeability transition

RBCs:

red blood cells

Rh123:

rhodamine 123

tBid:

truncated Bid

VDAC:

voltage-dependent anion channel

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Acknowledgements

We thank Drs H Terada and Y Shinohara for providing bongkrekic acid and SF6847. We are grateful to Dr M Forte for providing yeast strains (m3 and m22-2) and human vdac1 cDNA. We also thank Drs J Yuan, G Schatz, and CB Thompson for bid cDNA, the anti-yeast cytochrome c antibody, and bak+/− mice, respectively. This study was supported in part by a grant for Scientific Research on Priority Areas, a grant for Center of Excellence Research, a grant for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and by Special Coordination Funds of Promoting Science and Technology from the Science and Technology Agency of Japan.

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Authors and Affiliations

  1. Osaka University Medical School and Graduate School of Medicine, Laboratory of Molecular Genetics, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Tomoyasu Sugiyama, Shigeomi Shimizu & Yoshihide Tsujimoto

  2. Department of Cell Biology and Neuroscience, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Yosuke Matsuoka & Yoshihiro Yoneda

  3. Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Shigeomi Shimizu & Yoshihide Tsujimoto

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  1. Tomoyasu Sugiyama
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Correspondence to Yoshihide Tsujimoto.

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Sugiyama, T., Shimizu, S., Matsuoka, Y. et al. Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim. Oncogene 21, 4944–4956 (2002). https://doi.org/10.1038/sj.onc.1205621

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