Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions
Open accessAbstract
Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A–sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.
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MPT does not play a role in all forms of apoptosis.
“Formation of the pore can occur in response to many stimuli, including Ca2+ overload and oxidant stress, but MPT does not play a role in all forms of apoptosis (46, 125, 309, 438).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [125]
MPT pore formation can occur in response to many stimuli, including Ca2+ overload and oxidant stress.
“Formation of the pore can occur in response to many stimuli, including Ca2+ overload and oxidant stress, but MPT does not play a role in all forms of apoptosis (46, 125, 309, 438).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [125]
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Cites
Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., & Wang, X. (1997) · Cell · doi:10.1016/s0092-8674(00)80434-1 · Cited by 7,289 · see citing works
Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked
Yang, J., Liu, X., Bhalla, K. N., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T.-I., Jones, D. P., & Wang, X. (1997) · Science · doi:10.1126/science.275.5303.1129 · Cited by 4,913 · see citing works
The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis
Kluck, R. M., Bossy‐Wetzel, E., Green, D. R., & Newmeyer, D. D. (1997) · Science · doi:10.1126/science.275.5303.1132 · Cited by 4,715 · see citing works
The mitochondrial permeability transition
Zoratti, M., & Szabó, I. (1995) · Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes · doi:10.1016/0304-4157(95)00003-a · Cited by 2,395 · see citing works
The ATP synthase--a splendid molecular machine.
Boyer, P. (1997) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.66.1.717 · Cited by 1,913 · 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
The proto-oncogene Bcl-2 and its role in regulating apoptosis
Kroemer, G. (1997) · Nature Medicine · doi:10.1038/nm0697-614 · Cited by 1,739 · see citing works
Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S. A., Petit, P. X., Mignotte, B., & Kroemer, G. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.2.367 · Cited by 1,567 · see citing works
Bax directly induces release of cytochrome c from isolated mitochondria
Jürgensmeier, J. M., Xie, Z., Deveraux, Q. L., Ellerby, L., Bredesen, D. E., & Reed, J. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4997 · Cited by 1,523 · see citing works
Double identity for proteins of the Bcl-2 family
Reed, J. C. (1997) · Nature · doi:10.1038/42867 · Cited by 1,494 · see citing works
Mitochondrial control of apoptosis
Kroemer, G., Zamzami, N., & Susín, S. A. (1997) · Immunology Today · doi:10.1016/s0167-5699(97)80014-x · Cited by 1,492 · see citing works
X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death
Muchmore, S. W., Sattler, M., Liang, H., Meadows, R. P., Harlan, J. E., Yoon, H. S., Nettesheim, D. G., Chang, B. S., Thompson, C. B., Wong, S., et al. (1996) · Nature · doi:10.1038/381335a0 · Cited by 1,467 · see citing works
Bcl-xL Regulates the Membrane Potential and Volume Homeostasis of Mitochondria
Heiden, M. G. V., Chandel, N. S., Williamson, E. K., Schumacker, P. T., & Thompson, C. B. (1997) · Cell · doi:10.1016/s0092-8674(00)80450-x · Cited by 1,378 · see citing works
Mitochondrial control of nuclear apoptosis.
Zamzami, N., Susín, S. A., Marchetti, P., Hirsch, T., Gomez-Monterrey, I. M., Castedo, M., & Kroemer, G. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.4.1533 · Cited by 1,360 · see citing works
Bossy‐Wetzel, E., Newmeyer, D. D., & Green, D. R. (1998) · The EMBO Journal · doi:10.1093/emboj/17.1.37 · Cited by 1,225 · see citing works
Cytosol-to-membrane redistribution of Bax and Bcl-X L during apoptosis
Hsu, Y., Wolter, K. G., & Youle, R. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.3668 · Cited by 1,134 · see citing works
Inhibition of Bax Channel-Forming Activity by Bcl-2
Antonsson, B. E., Conti, F., Ciavatta, A., Montessuit, S., Lewis, S., Martinou, I., Bernasconi, L., Bernard, A., Mermod, J., Mazzei, G. J., et al. (1997) · Science · doi:10.1126/science.277.5324.370 · Cited by 1,028 · see citing works
Self-citationBAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases.
Xiang, J., Chao, D., & Korsmeyer, S. (1996) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.93.25.14559 · Cited by 988 · see citing works
Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c
Rossé, T., Olivier, R., Monney, L., Rager, M., Conus, S., Fellay, I., Jansen, B., & Borner, C. (1998) · Nature · doi:10.1038/35160 · Cited by 870 · see citing works
Mitochondrial permeability transition is a central coordinating event of apoptosis.
Marchetti, P., Castedo, M., Susín, S. A., Zamzami, N., Hirsch, T., Macho, A., Haeffner, A., Hirsch, F., Geuskens, M., & Kroemer, G. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.3.1155 · Cited by 847 · see citing works
Bcl-xL forms an ion channel in synthetic lipid membranes
Minn, A. J., Vélez, P., Schendel, S. L., Liang, H., Muchmore, S. W., Fesik, S. W., Fill, M., & Thompson, C. B. (1997) · Nature · doi:10.1038/385353a0 · Cited by 814 · see citing works
Ichas, F., Jouaville, L. S., & Mazat, J. (1997) · Cell · doi:10.1016/s0092-8674(00)80301-3 · Cited by 754 · see citing works
Marzo, I., Brenner, C., Zamzami, N., Susín, S. A., Beutner, G., Brdiczka, D. G., Rémy, R., Xie, Z.-H., Reed, J. C., & Kroemer, G. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.8.1261 · Cited by 684 · see citing works
Channel formation by antiapoptotic protein Bcl-2
Schendel, S. L., Xie, Z., Oblatt-Montal, M., Matsuyama, S., Montal, M., & Reed, J. C. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5113 · Cited by 602 · see citing works
Halestrap, A. P., Woodfield, K.-Y., & Connern, C. P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.6.3346 · Cited by 592 · see citing works
Newmeyer, D. (1994) · Cell · doi:10.1016/0092-8674(94)90203-8 · Cited by 581 · see citing works
Pastorino, J. G., Chen, S.-T., Tafani, M., Snyder, J. W., & Farber, J. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.13.7770 · Cited by 578 · see citing works
Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2
Schlesinger, P. H., Gross, A., Yin, X., Yamamoto, K., Saito, M. L., Waksman, G., & Korsmeyer, S. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.21.11357 · Cited by 492 · see citing works
Nicolli, A., Basso, E., Petronilli, V., Wenger, R. M., & Bernardi, P. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.4.2185 · Cited by 482 · see citing works
The permeability transition pore as a mitochondrial calcium release channel: A critical appraisal
Bernardi, P., & Petronilli, V. (1996) · Journal of Bioenergetics and Biomembranes · doi:10.1007/bf02110643 · Cited by 466 · see citing works
Mitochondrial ADP/ATP Carrier Can Be Reversibly Converted into a Large Channel by Ca 2+
Brustovetsky, N., & Klingenberg, M. (1996) · Biochemistry · doi:10.1021/bi960833v · Cited by 423 · see citing works
Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux
Shimizu, S., Eguchi, Y., Kamiike, W., Funahashi, Y., Mignon, A., Lacronique, V., Matsuda, H., & Tsujimoto, Y. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1455 · Cited by 410 · see citing works
Bcl-2 and Bax function independently to regulate cell death
Knudson, C. M., & Korsmeyer, S. J. (1997) · Nature Genetics · doi:10.1038/ng0897-358 · Cited by 400 · see citing works
Beutner, G., Rück, A., Riede, B., Welte, W., & Brdiczka, D. G. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)01092-7 · Cited by 337 · see citing works
Manon, S., Chaudhuri, B., & Guérin, M. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01087-9 · Cited by 297 · see citing works
Structure-Function Comparisons of the Proapoptotic Protein Bax in Yeast and Mammalian Cells
Zha, H., Fisk, H. A., Yaffe, M. P., Mahajan, N. P., Herman, B. A., & Reed, J. C. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.11.6494 · Cited by 282 · see citing works
Matsuyama, S., Xu, Q., Velours, J., & Reed, J. C. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80033-7 · Cited by 270 · see citing works
Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution
Kroemer, G. (1997) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400266 · Cited by 253 · see citing works
Pro‐oxidants and mitochondrial Ca2+: their relationship to apoptosis and oncogenesis
Richter, C. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)81423-w · Cited by 218 · see citing works
Self-citationRelease of Cytochrome c from Liver Mitochondria during Permeability Transition
Kantrow, S. P., & Piantadosi, C. A. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6353 · Cited by 197 · see citing works
Apoptosis: Bcl-2-related proteins get connected
Jacobson, M. D. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00136-9 · Cited by 103 · see citing works
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Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598 · see citing works
Mitochondrial control of cell death
Kroemer, G., & Reed, J. C. (2000) · Nature Medicine · doi:10.1038/74994 · Cited by 3,103 · see citing works
Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., Brunskill, E. W., Sayen, M. R., Gottlieb, R. A., Dorn, G. W., et al. (2005) · Nature · doi:10.1038/nature03434 · Cited by 2,280 · see citing works
Shimizu, S., Narita, M., Tsujimoto, Y., & Tsujimoto, Y. (1999) · Nature · doi:10.1038/20959 · Cited by 2,178 · see citing works
Nakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H., Inohara, H., Kubo, T., & Tsujimoto, Y. (2005) · Nature · doi:10.1038/nature03317 · Cited by 1,635 · see citing works
BCL-2 family proteins: changing partners in the dance towards death
Kale, J., Osterlund, E. J., & Andrews, D. W. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.186 · Cited by 1,574 · see citing works
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Scorrano, L., Ashiya, M., Buttle, K., Weiler, S., Oakes, S. A., Mannella, C. A., & Korsmeyer, S. J. (2002) · Developmental Cell · doi:10.1016/s1534-5807(01)00116-2 · Cited by 1,072 · see citing works
Butow, R. A., & Avadhani, N. G. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00179-0 · Cited by 882 · see citing works
Redox regulation of mitochondrial function
Handy, D. E., & Loscalzo, J. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4123 · Cited by 588 · see citing works
Control of mitochondrial permeability by Bcl-2 family members
Sharpe, J. C., Arnoult, D., & Youle, R. J. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2003.10.016 · Cited by 367 · see citing works
Brookes, P. S., Salinas, E. P., Darley-Usmar, K., Eiserich, J. P., Freeman, B. A., Darley-Usmar, V. M., & Anderson, P. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001077200 · Cited by 321 · see citing works
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Pilchova, I., Klacanova, K., Tatarkova, Z., Kaplan, P., & Racay, P. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/6797460 · Cited by 198 · see citing works
Bid acts on the permeability transition pore complex to induce apoptosis
Zamzami, N., Hamel, C. E., Maisse, C., Brenner, C., Muñoz-Pinedo, C., Belzacq, A.-S., Costantini, P., Vieira, H., Loeffler, M., Molle, G., et al. (2000) · Oncogene · doi:10.1038/sj.onc.1204030 · Cited by 178 · see citing works
Differential retrotranslocation of mitochondrial Bax and Bak
Todt, F., Cakir, Z., Reichenbach, F., Emschermann, F., Lauterwasser, J., Kaiser, A., Ichim, G., Tait, S. W., Frank, S., Langer, H. F., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201488806 · Cited by 172 · see citing works
Huang, H.-M., Zhang, H., Xu, H., & Gibson, G. E. (2003) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(02)00222-3 · Cited by 61 · see citing works
Regulation of neutrophil apoptosis
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- Authors
- Eskes, R., Antonsson, B., Osen-Sand, A., Montessuit, S., Richter, C., Sadoul, R., Mazzei, G., Nichols, A., & Martinou, J.-C.
- Affiliations
- ETH Zurich (CH)
- *Serono Pharmaceutical Research Institute, 1228 Plan-les-Ouates, Geneva, Switzerland; and ‡ ETH Laboratory of Biochemistry, 8092 Zurich, Switzerland
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 1998-10-05
- Volume
- 143
- Issue
- 1
- Pages
- 217-224
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2132823
- OpenAlex
- W2052793452
- Cited by
- 651
- References
- 41
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 14 · 2018: 15 · 2017: 10 · 2016: 10 · 2015: 14 · 2014: 12 · 2013: 15 · 2012: 14
- FWCI
- 21.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- 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, cytochrome c release, mitochondrial permeability transition pore, magnesium ions, apoptosis, Bcl-2 family proteins, cyclosporine, calcium, Apaf-1, caspase activation, mitochondrial outer membrane
- MeSH terms
- Animals, Bongkrekic Acid, Cytochrome c Group, Female, HeLa Cells, Humans, Intracellular Membranes, Magnesium, Mice, Inbred Strains, Mitochondria, Liver, Permeability, Proto-Oncogene Proteins, Recombinant Proteins, Transfection, Cyclosporine, Proto-Oncogene Proteins c-bcl-2, COS Cells, bcl-2-Associated X Protein, Mice
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