Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: a requirement for VDAC2 or Bak for efficient Bax apoptotic function
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In non-apoptotic cells, Bak constitutively resides in the mitochondrial outer membrane. In contrast, Bax is in a dynamic equilibrium between the cytosol and mitochondria, and is commonly predominant in the cytosol. In response to an apoptotic stimulus, Bax and Bak change conformation, leading to Bax accumulation at mitochondria and Bak/Bax oligomerization to form a pore in the mitochondrial outer membrane that is responsible for cell death. Using blue native-PAGE to investigate how Bax oligomerizes in the mitochondrial outer membrane, we observed that, like Bak, a proportion of Bax that constitutively resides at mitochondria associates with voltage-dependent anion channel (VDAC)2 prior to an apoptotic stimulus. During apoptosis, Bax dissociates from VDAC2 and homo-oligomerizes to form high molecular weight oligomers. In cells that lack VDAC2, constitutive mitochondrial localization of Bax and Bak was impaired, suggesting that VDAC2 has a role in Bax and Bak import to, or stability at, the mitochondrial outer membrane. However, following an apoptotic stimulus, Bak and Bax retained the ability to accumulate at VDAC2-deficient mitochondria and to mediate cell death. Silencing of Bak in VDAC2-deficient cells indicated that Bax required either VDAC2 or Bak in order to translocate to and oligomerize at the mitochondrial outer membrane to efficiently mediate apoptosis. In contrast, efficient Bak homo-oligomerization at the mitochondrial outer membrane and its pro-apoptotic function required neither VDAC2 nor Bax. Even a C-terminal mutant of Bax (S184L) that localizes to mitochondria did not constitutively target mitochondria deficient in VDAC2, but was recruited to mitochondria following an apoptotic stimulus dependent on Bak or upon over-expression of Bcl-xL. Together, our data suggest that Bax localizes to the mitochondrial outer membrane via alternate mechanisms, either constitutively via an interaction with VDAC2 or after activation via interaction with Bcl-2 family proteins.
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BAK constitutively resides at the OMM, where it inserts within the lipid bilayer via its hydrophobic C-terminal α9 helix upon interaction with VDAC2.
“In contrast, BAK constitutively resides at the OMM, where it inserts within the lipid bilayer via its hydrophobic C-terminal α9 helix upon interaction with voltage dependent anion channel 2 (VDAC2) [51–54].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [54]
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Cites
Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988 · see citing works
Shimizu, S., Narita, M., Tsujimoto, Y., & Tsujimoto, Y. (1999) · Nature · doi:10.1038/20959 · Cited by 2,178 · see citing works
Chen, L., Willis, S. N., Wei, A., Smith, B. J., Fletcher, J. I., Hinds, M. G., Colman, P. M., Day, C. L., Adams, J. M., & Huang, D. C. S. (2005) · Molecular Cell · doi:10.1016/j.molcel.2004.12.030 · Cited by 1,816 · see citing works
Movement of Bax from the Cytosol to Mitochondria during Apoptosis
Wolter, K. G., Hsu, Y., Smith, C. L., Nechushtan, A., Xi, X., & Youle, R. J. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.139.5.1281 · Cited by 1,809 · see citing works
Lindsten, T., Ross, A. J., King, A., Zong, W.-X., Rathmell, J. C., Shiels, H. A., Ulrich, E., Waymire, K. G., Mahar, P., Frauwirth, K., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00136-2 · Cited by 1,489 · see citing works
Willis, S. N., Chen, L., Dewson, G., Wei, A. H., Naik, E., Fletcher, J. I., Adams, J. M., & Huang, D. C. S. (2005) · Genes & Development · doi:10.1101/gad.1304105 · Cited by 1,236 · see citing works
Self-citationSuzuki, M., Youle, R. J., & Tjandra, N. (2000) · Cell · doi:10.1016/s0092-8674(00)00167-7 · Cited by 1,104 · see citing works
Korsmeyer, S. J., Wei, M. C., Saito, M., Weiler, S., Oh, K. J., & Schlesinger, P. H. (2000) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400783 · Cited by 1,034 · see citing works
VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis
Cheng, E. H.-Y., Sheiko, T. V., Fisher, J. K., Craigen, W. J., & Korsmeyer, S. J. (2003) · Science · doi:10.1126/science.1083995 · Cited by 852 · see citing works
Conformation of the Bax C‐terminus regulates subcellular location and cell death
Nechushtan, A., Smith, C. L., Hsu, Y., & Youle, R. J. (1999) · The EMBO Journal · doi:10.1093/emboj/18.9.2330 · Cited by 732 · see citing works
Bcl-xL Retrotranslocates Bax from the Mitochondria into the Cytosol
Edlich, F., Banerjee, S., Suzuki, M., Cleland, M. M., Arnoult, D., Wang, C., Neutzner, A., Tjandra, N., & Youle, R. J. (2011) · Cell · doi:10.1016/j.cell.2011.02.034 · Cited by 630 · see citing works
Stepwise Activation of BAX and BAK by tBID, BIM, and PUMA Initiates Mitochondrial Apoptosis
Kim, H., Tu, H.-C., Ren, D., Takeuchi, O., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., & Cheng, E. H.-Y. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.030 · Cited by 600 · see citing works
A Unified Model of Mammalian BCL-2 Protein Family Interactions at the Mitochondria
Llambi, F., Moldoveanu, T., Tait, S. W. G., Bouchier-Hayes, L., Temirov, J., McCormick, L. L., Dillon, C. P., & Green, D. R. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.10.001 · Cited by 596 · see citing works
Molecular biology of Bax and Bak activation and action
Westphal, D., Dewson, G., Czabotar, P. E., & Kluck, R. M. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.12.019 · Cited by 518 · see citing works
Self-citationHsu, Y., & Youle, R. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10777 · Cited by 504 · see citing works
Griffiths, G. J., Dubrez, L., Morgan, C. P., Jones, N. A., Whitehouse, J., Corfe, B. M., Dive, C., & Hickman, J. A. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.144.5.903 · Cited by 479 · see citing works
Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis
Annis, M. G., Soucie, E. L., Dlugosz, P. J., Cruz-Aguado, J. A., Penn, L. Z., Leber, B. F., & Andrews, D. W. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600675 · Cited by 377 · see citing works
To Trigger Apoptosis, Bak Exposes Its BH3 Domain and Homodimerizes via BH3:Groove Interactions
Dewson, G., Kratina, T., Sim, H. W., Puthalakath, H., Adams, J. M., Colman, P. M., & Kluck, R. M. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.005 · Cited by 348 · see citing works
Self-citationVDAC regulation by the Bcl-2 family of proteins
Tsujimoto, Y., & Shimizu, S. (2000) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400780 · Cited by 338 · see citing works
Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis
Rathmell, J. C., Lindsten, T., Zong, W., Cinalli, R. M., & Thompson, C. B. (2002) · Nature Immunology · doi:10.1038/ni834 · Cited by 297 · see citing works
Analysis of the Assembly Profiles for Mitochondrial- and Nuclear-DNA-Encoded Subunits into Complex I
Lazarou, M., McKenzie, M., Ohtake, A., Thorburn, D. R., & Ryan, M. T. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00074-07 · Cited by 254 · see citing works
Self-citationThe X-Ray Structure of a BAK Homodimer Reveals an Inhibitory Zinc Binding Site
Moldoveanu, T., Liu, Q., Tocilj, A., Watson, M., Shore, G. C., & Gehring, K. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.10.014 · Cited by 239 · see citing works
Schellenberg, B., Wang, P., Keeble, J. A., Rodriguez-Enriquez, R., Walker, S., Owens, T. W., Foster, F., Tanianis-Hughes, J., Brennan, K., Streuli, C. H., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.022 · Cited by 237 · see citing works
Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax
Fletcher, J. I., Meusburger, S., Hawkins, C. J., Riglar, D. T., Lee, E. F., Fairlie, W. D., Huang, D. C. S., & Adams, J. M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808691105 · Cited by 193 · see citing works
Bax dimerizes via a symmetric BH3:groove interface during apoptosis
Dewson, G., Ma, S., Frederick, P., Hockings, C., Tan, I., Kratina, T., & Kluck, R. M. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2011.138 · Cited by 189 · see citing works
Self-citationMediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein
Arbel, N., Ben-Hail, D., & Shoshan-Barmatz, V. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.345918 · Cited by 179 · see citing works
Molecular Details of Bax Activation, Oligomerization, and Membrane Insertion
Bleicken, S., Classen, M., Padmavathi, P. V. L., Ishikawa, T., Zeth, K., Steinhoff, H., & Bordignon, E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.081539 · Cited by 176 · see citing works
Setoguchi, K., Otera, H., & Mihara, K. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601438 · Cited by 163 · see citing works
Bellot, G., Cartron, P., Er, E., Oliver, L., Juin, P. P., Armstrong, L. C., BORNSTEIN, P. K., Mihara, K., Manon, S., & Vallette, F. M. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402055 · Cited by 156 · see citing works
Huang, H., Hu, X., Eno, C. O., Zhao, G., Li, C., & White, C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.448290 · Cited by 147 · see citing works
Roy, S. S., Ehrlich, A. M., Craigen, W. J., & Hajnóczky, G. (2009) · EMBO Reports · doi:10.1038/embor.2009.219 · Cited by 146 · see citing works
The C-terminal helix of Bcl-xL mediates Bax retrotranslocation from the mitochondria
Todt, F., Cakir, Z., Reichenbach, F., Youle, R. J., & Edlich, F. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.131 · Cited by 129 · see citing works
Inhibition of Bak Activation by VDAC2 Is Dependent on the Bak Transmembrane Anchor
Lazarou, M., Stojanovski, D., Frazier, A. E., Kotevski, A., Dewson, G., Craigen, W. J., Kluck, R. M., Vaux, D. L., & Ryan, M. T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159301 · Cited by 111 · see citing works
Self-citationOh, K. J., Singh, P., Lee, K., Foss, K., Lee, S., Park, M., Lee, S., Aluvila, S., Park, M., Singh, P., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.135293 · Cited by 87 · see citing works
Stroud, D. A., Formosa, L. E., Wijeyeratne, X. W., Nguyen, T. N., & Ryan, M. T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.c112.436766 · Cited by 82 · see citing works
Self-citationPutcha, G. V., Deshmukh, M., & Johnson, E. M. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.5.1011 · Cited by 73 · see citing works
Assembly of the Bak Apoptotic Pore
Ma, S., Hockings, C., Anwari, K., Kratina, T., Fennell, S., Lazarou, M., Ryan, M. T., Kluck, R. M., & Dewson, G. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.490094 · Cited by 71 · see citing works
Self-citationCrichton, P. G., Harding, M., Ruprecht, J. J., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.484329 · Cited by 64 · see citing works
The VDAC2-BAK Rheostat Controls Thymocyte Survival
Ren, D., Kim, H., Tu, H.-C., Westergard, T. D., Fisher, J. K., Rubens, J. A., Korsmeyer, S. J., Hsieh, J. J.-D., & Cheng, E. H. Y. (2009) · Science Signaling · doi:10.1126/scisignal.2000274 · Cited by 62 · see citing works
Requirement of voltage-dependent anion channel 2 for pro-apoptotic activity of Bax
Yamagata, H., Shimizu, S., Nishida, Y., Watanabe, Y., Craigen, W. J., & Tsujimoto, Y. (2009) · Oncogene · doi:10.1038/onc.2009.213 · Cited by 56 · see citing works
Bax targeting to mitochondria occurs via both tail anchor-dependent and -independent mechanisms
Valentijn, A., Upton, J.-P., Bates, N., et al. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.39 · Cited by 53 · see citing works
Ross, K., Rudel, T., & Kozjak‐Pavlovic, V. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2008.194 · Cited by 44 · see citing works
Valentijn, A., Upton, J.-P., & Gilmore, A. P. (2008) · Biochemical Journal · doi:10.1042/bj20071548 · Cited by 37 · see citing works
Vogel, S., Raulf, N., Bregenhorn, S., Biniossek, M. L., Maurer, U., Czabotar, P. E., & Borner, C. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.248906 · Cited by 33 · see citing works
Huckabee, D. B., & Jekabsons, M. B. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07499.x · Cited by 17 · see citing works
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- Authors
- Ma, S. B., Nguyen, T. N., Tan, I., Ninnis, R., Iyer, S., Stroud, D. A., Menard, M., Kluck, R. M., Ryan, M. T., & Dewson, G.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- La Trobe University (AU)
- The University of Melbourne (AU)
- Corresponding author
- Dewson, G
- Venue
- Cell Death & Differentiation
- Published
- 2014-08-22
- Volume
- 21
- Issue
- 12
- Pages
- 1925-1935
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC4227151
- OpenAlex
- W2020418292
- Cited by
- 138
- References
- 45
- Citations by year
- 2026: 11 · 2025: 6 · 2024: 13 · 2023: 10 · 2022: 10 · 2021: 8 · 2020: 11 · 2019: 13 · 2018: 14 · 2017: 17 · 2016: 15 · 2015: 9
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian Government
- Stanford Institute for Research in the Social Sciences
- Medical Research Council
- National Health and Medical Research Council (637335)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Bax, Bak, VDAC2, mitochondrial outer membrane, apoptosis, Bax oligomerization, mitochondrial targeting, Bcl-2 family proteins, Bcl-xL, mitochondrial permeability transition pore
- MeSH terms
- Animals, Cells, Cultured, Mice, Inbred C57BL, Mitochondria, Apoptosis, Mice, Knockout, Protein Transport, Voltage-Dependent Anion Channel 2, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Protein Multimerization, Mice, 129 Strain
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