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Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC

Author

Listed:
  • Shigeomi Shimizu

    (CREST of Japan Science and Technology Corporation (JST))

  • Masashi Narita

    (Osaka University Medical School, Biomedical Research Center)

  • Yoshihide Tsujimoto

    (CREST of Japan Science and Technology Corporation (JST))

  • Yoshihide Tsujimoto

    (Correspondence and requests for materials should be addressed to Y.T. (e-mail: .))

Abstract

During transduction of an apoptotic (death) signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases1,2. The Bcl-2 family of proteins, whose members may be anti-apoptotic or pro-apoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis3,4,5, but how that is achieved is unclear. Here we create liposomes that carry the mitochondrial porin channel (also called the voltage-dependent anion channel, or VDAC) to show that the recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-xL closes VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by Bcl-xL. In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by Bcl-xL. Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.

Suggested Citation

  • Shigeomi Shimizu & Masashi Narita & Yoshihide Tsujimoto & Yoshihide Tsujimoto, 1999. "Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC," Nature, Nature, vol. 399(6735), pages 483-487, June.
    • Handle: RePEc:nat:nature:v:399:y:1999:i:6735:d:10.1038_20959
    DOI: 10.1038/20959
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    Cited by:

    1. Manna, Smarajit & Banerjee, Jyotirmoy & Ghosh, Subhendu, 2007. "Breathing of voltage dependent anion channel as revealed by the fractal property of its gating," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 386(1), pages 573-580.
    2. Yao-Zhong Liu & Yu Zhou & Lei Zhang & Jian Li & Qing Tian & Ji-Gang Zhang & Hong-Wen Deng, 2015. "Attenuated Monocyte Apoptosis, a New Mechanism for Osteoporosis Suggested by a Transcriptome-Wide Expression Study of Monocytes," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-18, February.
    3. Shintaro Mise & Akinobu Matsumoto & Keisuke Shimada & Toshiaki Hosaka & Masatomo Takahashi & Kazuya Ichihara & Hideyuki Shimizu & Chisa Shiraishi & Daisuke Saito & Mikita Suyama & Tomoharu Yasuda & To, 2022. "Kastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Claire Grills & Puthen V Jithesh & Jaine Blayney & Shu-Dong Zhang & Dean A Fennell, 2011. "Gene Expression Meta-Analysis Identifies VDAC1 as a Predictor of Poor Outcome in Early Stage Non-Small Cell Lung Cancer," PLOS ONE, Public Library of Science, vol. 6(1), pages 1-8, January.

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