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  • Original Paper
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Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator

Oncogene volume 19, pages 4309–4318 (2000)Cite this article

Abstract

Mitochondria play an essential role in apoptosis by releasing apoptogenic molecules such as cytochrome c and AIF, and some caspases, which are all regulated by Bcl-2 family proteins. Pro-apoptotic Bax and Bak have been shown to induce cytochrome c release and loss of membrane potential (Δψ) leading to AIF release in the isolated mitochondria. We have previously shown that Bax and Bak open the voltage-dependent anion channel (VDAC) allowing cytochrome c to pass through the channel, and Bcl-xL closes the channel. However, it has been reported that it is adenine nucleotide translocator (ANT) with which Bax/Bcl-xL interacts that modulate the channel activity. Here, we investigated the role of ANT and VDAC in the changes of isolated mitochondria triggered by Bax and by chemicals that induce permeability transition (PT). In rat and yeast mitochondria, Bax did not affect the ADP/ATP exchange activity of ANT. VDAC-deficient but not ANT-deficient yeast mitochondria showed resistance to cytochrome c release, Δψ loss, and swelling caused by Bax and PT inducers. Bcl-xL showed similar inhibition of all these changes in ANT-deficient and wild type yeast mitochondria. Furthermore, Bax induces cytochrome c release in wild type yeast cells but not VDAC1-deficient yeast cells. These data indicate that VDAC, but not ANT, is essential for apoptotic mitochondrial changes. The data also indicate that Bcl-xL and Bax possess an ability to regulate mitochondrial membrane permeability independently of other Bcl-2 family members.

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Abbreviations

PT:

permeability transition

AIF:

apoptosis-inducing factor

ANT:

adenine nucleotide translocator

VDAC:

voltage-dependent anion channel

GST:

glutathione S-transferase

DTBP:

Dimethyl 3, 3′-dithiobispropionimidate [2HCl]

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Acknowledgements

We are grateful to Dr G Schatz for providing anti-yeast cytochrome c antibody, Dr M Forte for VDAC1-deficient yeast (M22-2), its wild type (M3), and human vdac1 cDNA, Dr MG Douglas for ANT3-deficient yeast (WΔ3) and its wild type (M3). This study was supported in part by a grant for Scientific Research on Priority Areas, by a grant for Center of Excellence Research, and by a grant for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, and by Special Coordination Funds for Promoting Science and Technology from the Science and Technology Agency of Japan.

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Authors and Affiliations

  1. Department of Medical Genetics, Osaka University Graduate School of Medicine, Biomedical Research Center, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Shigeomi Shimizu & Yoshihide Tsujimoto

  2. Faculty of Pharmaceutical Sciences, University of Tokushima, Shomachi-1, Tokushima, 770-8505, Japan

    Yasuo Shinohara

  3. Core Research for Evolutional Science, Japan Science and Technology Corp. (JST), Japan

    Shigeomi Shimizu & Yoshihide Tsujimoto

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  1. Shigeomi Shimizu
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Shimizu, S., Shinohara, Y. & Tsujimoto, Y. Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator. Oncogene 19, 4309–4318 (2000). https://doi.org/10.1038/sj.onc.1203788

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