VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis
Abstract
The multidomain proapoptotic molecules BAK or BAX are required to initiate the mitochondrial pathway of apoptosis. How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown. In viable cells, we found BAK complexed with mitochondrial outer-membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate “BH3-only” molecules such as tBID, BIM, or BAD, which displace VDAC2 from BAK, enabling homo-oligomerization of BAK and apoptosis. Thus, VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.
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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 [51]
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- Authors
- Cheng, E. H.-Y., Sheiko, T. V., Fisher, J. K., Craigen, W. J., & Korsmeyer, S. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Korsmeyer, Stanley J.
- ORCID
- Cheng, Emily H.-Y.
- Venue
- Science
- Published
- 2003-07-25
- Volume
- 301
- Issue
- 5632
- Pages
- 513-517
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1988917342
- Cited by
- 852
- References
- 27
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 26 · 2023: 32 · 2022: 19 · 2021: 33 · 2020: 24 · 2019: 26 · 2018: 32 · 2017: 38 · 2016: 29 · 2015: 38 · 2014: 32 · 2013: 35 · 2012: 45
- FWCI
- 18.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R37 CA50239, R37CA050239)
- National Institute of Neurological Disorders and Stroke (NS42319)
- 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
- VDAC2, Bak, mitochondrial apoptosis, Bak activation, VDAC1, mitochondrial outer membrane, BH3-only proteins, tBid, building information modeling, Bad, mitochondrial permeability transition pore
- MeSH terms
- Animals, Biopolymers, Carrier Proteins, Cell Line, Cells, Cultured, Etoposide, Humans, Intracellular Membranes, Membrane Proteins, Mice, Inbred C57BL, Mitochondria, Mitochondria, Liver, Protein Binding, Protein Conformation, Proto-Oncogene Proteins, Recombinant Proteins, Apoptosis, Protein Structure, Tertiary, Porins, Jurkat Cells, Proto-Oncogene Proteins c-bcl-2, Staurosporine, Voltage-Dependent Anion Channels, Voltage-Dependent Anion Channel 1, Voltage-Dependent Anion Channel 2, bcl-2 Homologous Antagonist-Killer Protein, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mice
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