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Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death


Mitochondria are critically involved in necrotic cell death induced by Ca2+ overload, hypoxia and oxidative damage. The mitochondrial permeability transition (MPT) pore — a protein complex that spans both the outer and inner mitochondrial membranes — is considered the mediator of this event and has been hypothesized to minimally consist of the voltage-dependent anion channel (Vdac) in the outer membrane, the adenine-nucleotide translocase (Ant) in the inner membrane and cyclophilin-D in the matrix1,2,3. Here, we report the effects of deletion of the three mammalian Vdac genes on mitochondrial-dependent cell death. Mitochondria from Vdac1-, Vdac3-, and Vdac1Vdac3-null mice exhibited a Ca2+- and oxidative stress-induced MPT that was indistinguishable from wild-type mitochondria. Similarly, Ca2+- and oxidative-stress-induced MPT and cell death was unaltered, or even exacerbated, in fibroblasts lacking Vdac1, Vdac2, Vdac3, Vdac1–Vdac3 and Vdac1–Vdac2–Vdac3. Wild-type and Vdac-deficient mitochondria and cells also exhibited equivalent cytochrome c release, caspase cleavage and cell death in response to the pro-death Bcl-2 family members Bax and Bid. These results indicate that Vdacs are dispensable for both MPT and Bcl-2 family member-driven cell death.

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Figure 1: Mitochondrial permeability transition in Vdac1- and Vdac3-deficient mitochondria.
Figure 2: Cytochrome c release induced by Ca2+, oxidative stress, Bax and tBid.
Figure 3: Mitochondrial permeability transition and cell death in Vdac1- and Vdac3-null MEFs.
Figure 4: Cell death in Vdac-deficient MEFs.
Figure 5: MPT and cell death in Vdac2-null fibroblasts and in MEFs deficient in Vdac proteins.


  1. Zamzami, N. & Kroemer G. The mitochondrion in apoptosis: how Pandora's box opens. Nature Rev. Mol. Cell. Biol. 2, 67–71 (2001).

    CAS  Article  Google Scholar 

  2. Crompton, M., Barksby, E., Johnson, N. & Capano, M. Mitochondrial intermembrane junctional complexes and their involvement in cell death. Biochimie 84, 143–152 (2002).

    CAS  Article  Google Scholar 

  3. Halestrap, A. P. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem. Soc. Trans. 34, 232–237 (2006).

    CAS  Article  Google Scholar 

  4. Rostovtseva, T. K., Tan, W. & Colombini, M. On the role of VDAC in apoptosis: fact and fiction. J. Bioenerg. Biomembr. 37, 129–142 (2005).

    CAS  Article  Google Scholar 

  5. Blachly-Dyson. E. & Forte, M. VDAC channels. IUBMB Life 52, 113–118 (2001).

    CAS  Article  Google Scholar 

  6. Wu, S., Sampson, M. J., Decker, W. K. & Craigen, W. J. Each mammalian mitochondrial outer membrane porin protein is dispensable: effects on cellular respiration. Biochim. Biophys. Acta. 1452, 68–78 (1999).

    CAS  Article  Google Scholar 

  7. Anflous, K., Armstrong, D. D. & Craigen, W. J. Altered mitochondrial sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice. J. Biol. Chem. 276, 1954–1960 (2001).

    CAS  Article  Google Scholar 

  8. Sampson, M. J. et al. Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J. Biol. Chem. 276, 39206–39212 (2001).

    CAS  Article  Google Scholar 

  9. Krauskopf, A., Eriksson, O., Craigen, W. J., Forte, M. A. & Bernardi, P. Properties of the permeability transition in VDAC1−/− mitochondria. Biochim. Biophys. Acta. 1757, 590–595 (2006).

    CAS  Article  Google Scholar 

  10. Sheiko, T. V., Fisher, J. K., Craigen, W. J. & Korsmeyer, S. J. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301, 513–517 (2003).

    Article  Google Scholar 

  11. Banerjee, J. & Ghosh, S. Bax increases the pore size of rat brain mitochondrial voltage-dependent anion channel in the presence of tBid. Biochem. Biophys. Res. Commun. 323, 310–314 (2004).

    CAS  Article  Google Scholar 

  12. Shimizu, S., Ide, T., Yanagida, T. & Tsujimoto, Y. Electrophysiological study of a novel large pore formed by Bax and the voltage-dependent anion channel that is permeable to cytochrome c. J. Biol. Chem. 275, 12321–12325 (2000).

    CAS  Article  Google Scholar 

  13. Sugiyama, T., Shimizu, S., Matsuoka, Y., Yoneda, Y. & Tsujimoto, Y. Activation of mitochondrial voltage-dependent anion channel by a pro-apoptotic BH3-only protein Bim. Oncogene 21, 4944–4956 (2002).

    CAS  Article  Google Scholar 

  14. Shimizu, S., Narita, M. & Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399, 483–487 (1999).

    CAS  Article  Google Scholar 

  15. Petronilli, V. et al. Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys. J. 76, 725–734 (1999).

    CAS  Article  Google Scholar 

  16. Baines, C. P. et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662 (2005).

    CAS  Article  Google Scholar 

  17. Bernardi, P. et al. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS. J. 273, 2077–2099 (2006).

    CAS  Article  Google Scholar 

  18. Halestrap, A. P., McStay, G. P. & Clarke, S. J. The permeability transition pore complex: another view. Biochimie 84, 153–166 (2002).

    CAS  Article  Google Scholar 

  19. Nakagawa, T. et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652–658 (2005).

    CAS  Article  Google Scholar 

  20. Basso, E. et al. Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J. Biol. Chem. 280, 18558–18561 (2005).

    CAS  Article  Google Scholar 

  21. Schinzel, A. C. et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl Acad. Sci. USA 102, 12005–12010 (2005).

    CAS  Article  Google Scholar 

  22. Kokoszka, J. E. et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427, 461–465 (2004).

    CAS  Article  Google Scholar 

  23. Crompton, M., Virji, S. & Ward, J. M. Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur. J. Biochem. 258, 729–735 (1998).

    CAS  Article  Google Scholar 

  24. Woodfield, K., Ruck, A., Brdiczka, D. & Halestrap, A. P. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem. J. 336, 287–290 (1998).

    CAS  Article  Google Scholar 

  25. Vander Heiden, M. G., et al. Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc. Natl Acad. Sci. USA 97, 4666–4671 (2000).

    CAS  Article  Google Scholar 

  26. Vander Heiden, M. G. et al. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J. Biol. Chem. 276, 19414–19419 (2001).

    CAS  Article  Google Scholar 

  27. Lai, J. C. et al. A pharmacologic target of G3139 in melanoma cells may be the mitochondrial VDAC. Proc. Natl Acad. Sci. USA 103, 7494–7499 (2006).

    CAS  Article  Google Scholar 

  28. Priault, M., Chaudhuri, B., Clow, A., Camougrand, N. & Manon, S. Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of mitochondrial membranes, role of VDAC and ATP requirement. Eur. J. Biochem. 260, 684–691 (1999).

    CAS  Article  Google Scholar 

  29. Polcic, P. & Forte, M. Response of yeast to the regulated expression of proteins in the Bcl-2 family. Biochem. J. 374, 393–402 (2003).

    CAS  Article  Google Scholar 

  30. Rostovtseva, T. K. et al. Bid, but not Bax, regulates VDAC channels. J. Biol. Chem. 279, 13575–13583 (2004).

    CAS  Article  Google Scholar 

  31. Antonsson, B., Montessuit, S., Lauper, S., Eskes, R. & Martinou, J. C. Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem. J. 345, 271–278 (2000).

    CAS  Article  Google Scholar 

  32. Kagawa, S., et al. A binary adenoviral vector system for expressing high levels of the proapoptotic gene bax. Gene Ther. 7, 75–79 (2000).

    CAS  Article  Google Scholar 

  33. Kaiser, R. A., et al. Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J. Biol. Chem. 279, 15524–15530 (2004).

    CAS  Article  Google Scholar 

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We are very grateful to B. Fang for the generous gift of the Bax adenovirus, R. Gottlieb for recombinant Bax and tBid, and the late S. Korsmeyer for Bax–Bak gene-targeted mice. This work was supported by grants from the National Institutes of Health (J.D.M. and W.J.C.), an American Heart Association Scientist Development Grant (C.P.B.) and Established Investigator Grant (J.D.M.), a National Institutes of Health NRSA award (R.A.K.), The Children's Hospital Research Foundation (C.P.B.), and the Fondation Leducq (Heart failure network grant to J.D.M).

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C.P.B. and J.D.M. conceived the research project, C.P.B. performed all experimentation except the ischaemia–reperfusion experiment, which was performed by R.A.K. T.S. and W.J.C. provided critical reagents and valuable discussion.

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Correspondence to Jeffery D. Molkentin.

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The authors declare no competing financial interests.

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Baines, C., Kaiser, R., Sheiko, T. et al. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9, 550–555 (2007).

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