Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC
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 caspases. 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 apoptosis, 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-x(L) 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-x(L). 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-x(L). 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.
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Pro- and anti-apoptotic BCL2 family members such as BAX, BAK, BID, BCL2, and BCL-XL regulate MPT-driven necrosis.
“These include: (1) pro- and anti-apoptotic BCL2 family members such as BAX, BAK, and BID [407–410], as well as BCL2 and BCL-XL [411–414]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [412]
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- Authors
- Shimizu, S., Narita, M., Tsujimoto, Y., & Tsujimoto, Y.
- Affiliations
- Japan Science and Technology Agency (JP)
- The University of Osaka (JP)
- Venue
- Nature
- Published
- 1999-06-03
- Volume
- 399
- Issue
- 6735
- Pages
- 483-487
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1644794975
- Cited by
- 2,178
- References
- 30
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 24 · 2023: 29 · 2022: 35 · 2021: 59 · 2020: 43 · 2019: 32 · 2018: 52 · 2017: 59 · 2016: 55 · 2015: 65 · 2014: 68 · 2013: 72 · 2012: 62
- FWCI
- 62.65
- Type
- journal article
- Language
- en
- Update notices
- erratum (2000-10-12)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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 › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- Bcl-2 family proteins, cytochrome c release, voltage-dependent anion channel, mitochondrial permeability transition, apoptosis, Bax, Bak, Bcl-xL, mitochondrial membrane potential, caspase activation
- MeSH terms
- Mitochondrial ADP, ATP Translocases, Animals, Cytochrome c Group, Humans, Intracellular Membranes, Ion Channels, Liposomes, Membrane Potentials, Membrane Proteins, Mitochondria, Mitochondria, Liver, Proto-Oncogene Proteins, Sucrose, Apoptosis, Porins, Proto-Oncogene Proteins c-bcl-2, Voltage-Dependent Anion Channels, Voltage-Dependent Anion Channel 1, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein, bcl-2-Associated X Protein, Rats
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