Affinage

VDAC2

Non-selective voltage-gated ion channel VDAC2 · UniProt P45880

Length
294 aa
Mass
31.6 kDa
Annotated
2026-06-11
77 papers in source corpus 36 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VDAC2 is a mitochondrial outer membrane β-barrel porin that functions as an isoform-specific gatekeeper of the intrinsic apoptotic machinery, distinct from VDAC1 and VDAC3 in its dedicated regulation of the BCL-2 effectors BAK and BAX (PMID:12881569, PMID:19820692, PMID:30478310). In viable cells VDAC2 holds BAK in an inactive monomeric conformation within a ~400 kDa complex, engaging the hydrophobic transmembrane anchor of BAK to sequester it; death signals acting through BH3-only proteins (tBID, BIM, BAD) or the pro-apoptotic BCL-xS displace VDAC2 from BAK to license BAK homo-oligomerization and apoptosis (PMID:12881569, PMID:20851889, PMID:22705850). VDAC2 is also required for the constitutive mitochondrial recruitment of BAK and BAX and for BAX retrotranslocation back to the cytosol, so that loss of VDAC2 mislocalizes these effectors and selectively abrogates BAX-dependent killing while redirecting BAK to peroxisomes to cause peroxisomal membrane permeabilization (PMID:19820692, PMID:25146925, PMID:27620692, PMID:28174205, PMID:30478310). The precise residues of the cytosol-exposed VDAC2 surface and the BAK BH3 domain/hydrophobic groove that form this interface have been mapped, and the interaction is pharmacologically tractable, with small molecules that bind VDAC2 either inhibiting or priming BAK-driven death (PMID:31591564, PMID:38696533). In vivo this VDAC2–BAK rheostat sets thresholds for thymocyte survival and tumor-cell death, and acts as an innate-immune checkpoint that restrains IFNγ-induced BAK activation, mitochondrial DNA release, and cGAS-STING signaling (PMID:19706873, PMID:40108474, PMID:40069152). Beyond apoptosis, VDAC2 binds ceramides directly at a membrane-buried glutamate to mediate ceramide-induced cell death, and serves as a contact-site scaffold and metabolic regulator: it interacts with StAR at mitochondria-associated ER membranes to permit steroidogenesis, recruits GSK-3β to drive mitochondrial permeability transition pore opening, restrains PFKP-mediated glycolysis, and tethers Ras-PI3K endosomes to mitochondria (PMID:25505173, PMID:25187518, PMID:30250190, PMID:31015432, PMID:36906852). VDAC2 abundance and activity are tuned by post-translational modification, including Nedd4- and TRIM8-mediated ubiquitination and proteasomal degradation that govern ferroptosis sensitivity, and IFIT3-assisted O-GlcNAcylation by OGT that protects against chemotherapy-induced apoptosis (PMID:31974380, PMID:32641986, PMID:38881325).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    Established that VDAC2 is not merely a generic porin but an isoform-specific brake on apoptosis, answering how inactive BAK is held in check in healthy cells.

    Evidence Co-IP, VDAC2-knockout MEFs, overexpression and apoptosis assays showing VDAC2 binds inactive BAK and BH3-only proteins displace it

    PMID:12881569

    Open questions at the time
    • Structural basis of the VDAC2–BAK contact not resolved
    • Whether channel conductance contributes to sequestration untested
  2. 2009 High

    Showed VDAC2 is required to recruit BAK to mitochondria and to confer tBID sensitivity, and that this controls thymocyte homeostasis in vivo, distinguishing it from VDAC1/VDAC3.

    Evidence Isoform-specific KO MEFs with cytochrome c release and reconstitution; conditional KO mice with Bak/Bax epistasis

    PMID:19706873 PMID:19820692

    Open questions at the time
    • Mechanism of mitochondrial targeting via VDAC2 not defined
    • Does not address BAX recruitment
  3. 2010 High

    Defined the physical basis of sequestration: VDAC2 engages the BAK transmembrane tail anchor within a ~400 kDa complex from which BAK is released upon activation.

    Evidence Blue native-PAGE and BAK transmembrane-domain mutagenesis with apoptosis readouts

    PMID:20851889

    Open questions at the time
    • Other complex components beyond VDAC2 not identified
    • No atomic-resolution interface
  4. 2012 Medium

    Identified BCL-xS as a proapoptotic ligand that works indirectly by displacing BAK from VDAC2, reinforcing the displacement model.

    Evidence Reciprocal Co-IP, Bak knockdown and VDAC2 overexpression in melanoma cells

    PMID:22705850

    Open questions at the time
    • Single lab
    • Direct competition for the same VDAC2 surface not structurally demonstrated
  5. 2014 High

    Extended VDAC2's role to BAX, showing it governs constitutive mitochondrial localization of both effectors, and identified its partnership with StAR and GSK-3β at contact sites.

    Evidence Blue native-PAGE and KO/silencing epistasis for BAX/BAK; Co-IP with domain mutagenesis for StAR; MS-based identification and isoform-specific siRNA for GSK-3β with mPTP readouts

    PMID:25146925 PMID:25187518 PMID:25505173

    Open questions at the time
    • How VDAC2 discriminates BAX from BAK regulation unresolved
    • Channel function versus scaffolding contribution not separated
  6. 2016 High

    Defined VDAC2 as the platform that ensures mitochondria-specific BAX/BAK membrane association and retrotranslocation, and revealed that its loss redirects BAK to permeabilize peroxisomes.

    Evidence VDAC2 KO with BAX retrotranslocation assays, peroxisomal fractionation and genetic rescue with BAK inhibitors

    PMID:27620692 PMID:28174205

    Open questions at the time
    • Determinants of organelle targeting selectivity unknown
    • Mechanism of retrotranslocation not reconstituted
  7. 2017 Medium

    Linked VDAC2 to metabolic control by showing it binds PFKP to restrain glycolysis and suppress glioma stem-cell reprogramming.

    Evidence Co-IP, loss/gain-of-function with glycolysis and sphere-formation assays plus pharmacological rescue

    PMID:30250190

    Open questions at the time
    • Single lab
    • Whether channel activity is required for PFKP regulation untested
  8. 2018 High

    Unbiased genome-wide screening established VDAC2 as selectively essential for BAX, not BAK, apoptotic function, refining the dual-effector model.

    Evidence Genome-wide CRISPR screen, genetic deletion, blue native-PAGE and in vivo tumor assays

    PMID:30478310

    Open questions at the time
    • Reconciliation with BAK-sequestration role context-dependent
    • Structural basis of differential effector handling open
  9. 2019 High

    Demonstrated a channel-wall ceramide binding site at a membrane-buried glutamate making VDAC2 the direct effector of ceramide-induced apoptosis, and showed the BAK interface is druggable.

    Evidence Photoaffinity ceramide crosslinking, E→Q mutagenesis, KO rescue and MD; WEHI-9625 binding with clonogenic/apoptosis assays; Noxa eMTD Co-IP and mPTP assays

    PMID:31015432 PMID:31285435 PMID:31591564

    Open questions at the time
    • Physiological ceramide pools engaging VDAC2 in vivo unmapped
    • WEHI-9625 mechanism species-specific (mouse BAK)
  10. 2020 Medium

    Established VDAC2 abundance and activity as a node controlled by ubiquitination, O-GlcNAcylation and contact-site partners, tuning ferroptosis and apoptosis sensitivity.

    Evidence Ubiquitination assays identifying Nedd4 with ferroptosis readouts; MS/Co-IP for IFIT3-OGT-driven O-GlcNAcylation with chemo-sensitivity; Co-IP for STING and palmitoylated CKAP4 at ER-mito contacts with Ca2+/signaling assays; BAX retrotranslocation

    PMID:31974380 PMID:32641986 PMID:33067255 PMID:36445063

    Open questions at the time
    • Modified residues for ubiquitin/O-GlcNAc not all mapped
    • Crosstalk between distinct PTMs untested
  11. 2023 Medium

    Showed PTMs on the VDAC2 N-terminus (K46 malonylation) reprogram its structure to drive mitochondrial ferroptosis, and identified additional small-molecule and endosomal-scaffold functions.

    Evidence MS-identified malonylation with K46 mutagenesis, MD/CD and ferroptosis assays; celastrol chemical proteomics with mPTP/ferroptosis readouts; Co-IP and optogenetics for VDAC2-PI3K endosome tethering

    PMID:30250190 PMID:36906852 PMID:37416771 PMID:38149060

    Open questions at the time
    • Single labs
    • Direct link between N-terminal structural change and channel gating untested
  12. 2024 High

    Mapped the precise BAK-VDAC2 interaction interface and characterized further degradation control (TRIM8) and structural features stabilizing VDAC2.

    Evidence Deep scanning mutagenesis with cysteine crosslinking and apoptosis assays; TRIM8 Co-IP/ubiquitination with ferroptosis rescue; high-resolution MS of intramolecular disulfide bridges

    PMID:38696533 PMID:38832804 PMID:38881325

    Open questions at the time
    • No co-crystal/cryo-EM of the complex
    • Functional roles of individual disulfides not tested
  13. 2025 High

    Established VDAC2 as an innate-immune checkpoint whose loss unleashes IFNγ-induced BAK activation, mtDNA release and cGAS-STING signaling, and demonstrated its tissue-specific therapeutic window in liver cancer.

    Evidence Genome-scale CRISPR genetic-interaction screens with BAK epistasis and cGAS-STING assays; VDAC2/BAK expression and tBID-permeabilization assays with BCL-2 inhibitor combinations in hepatocarcinoma models

    PMID:40069152 PMID:40108474

    Open questions at the time
    • How IFNγ tips the VDAC2-BAK balance mechanistically unresolved
    • Selectivity of therapeutic window across tissues not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the porin/channel conductance activity of VDAC2 is mechanistically separable from its scaffolding/sequestration of BCL-2 effectors and contact-site partners remains unresolved.
  • No high-resolution structure of VDAC2 bound to BAK, BAX, ceramide or partners
  • Causal role of channel gating in apoptotic/metabolic functions untested
  • Integration of multiple PTMs into a single regulatory logic unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0060090 molecular adaptor activity 4 GO:0140313 molecular sequestering activity 3 GO:0008289 lipid binding 1
Localization
GO:0005739 mitochondrion 4 GO:0005783 endoplasmic reticulum 2 GO:0005777 peroxisome 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-1430728 Metabolism 1 R-HSA-168256 Immune System 1
Partners
BAK1BAXBECN1CKAP4GSK3BPFKPSTARSTING1
Complex memberships
VDAC2-BAK inactive complexVDAC2-BECN1-BCL2L1 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 In viable cells, BAK is complexed with VDAC2 at the mitochondrial outer membrane in an inactive monomeric conformation. VDAC2 specifically interacts with the inactive conformer of BAK, and cells deficient in VDAC2 (but not VDAC1) exhibit enhanced BAK oligomerization and increased susceptibility to apoptosis. Overexpression of VDAC2 selectively prevents BAK activation. Death signals activate BH3-only molecules (tBID, BIM, BAD) that displace VDAC2 from BAK, enabling BAK homo-oligomerization and apoptosis. Co-immunoprecipitation, VDAC2 knockout MEFs, overexpression studies, apoptosis assays Science High 12881569
2009 VDAC2 is required for mitochondrial recruitment of BAK. VDAC2-deficient MEFs lack mitochondrial BAK despite normal total BAK expression, and are virtually insensitive to tBID-induced outer mitochondrial membrane permeabilization and apoptosis. VDAC1-/-, VDAC3-/-, and VDAC1-/-/VDAC3-/- MEFs respond normally to tBID. Reintroduction of VDAC2 restores tBID sensitivity. Addition of recombinant BAX can also restore sensitivity in VDAC2-/- MEFs. VDAC isoform-specific knockout MEFs, cytochrome c release assays, mitochondrial fractionation, recombinant protein reconstitution EMBO reports High 19820692
2009 The VDAC2-BAK rheostat controls thymocyte survival in vivo. Genetic depletion of Vdac2 in the thymus causes excessive cell death and hypersensitivity to diverse death stimuli including TCR engagement. These phenotypes are completely rescued by concurrent deletion of Bak but not Bax, establishing that the VDAC2-BAK axis governs thymocyte homeostasis. Conditional genetic knockout mice, epistasis analysis (double KO), in vivo thymocyte survival assays Science Signaling High 19706873
2010 Inactive BAK exists in a ~400 kDa complex dependent on VDAC2. BAK activation is concomitant with its release from this complex. VDAC2 interacts with the hydrophobic transmembrane anchor (tail) of BAK to sequester it in an inactive state. Substitution of the BAK transmembrane anchor with that of hFis1 prevents association with the VDAC2 complex and increases apoptotic sensitivity. Blue native-PAGE, site-directed mutagenesis of BAK transmembrane domain, apoptosis assays Journal of Biological Chemistry High 20851889
2012 BCL-xS interacts with VDAC2 in melanoma cells (confirmed by reciprocal co-immunoprecipitation). BCL-xS binding to VDAC2 disrupts the VDAC2-BAK interaction, releasing BAK for activation and apoptosis. BCL-xS shows no direct interaction with BAK; its proapoptotic effect is mediated through displacement of BAK from VDAC2. Overexpression of VDAC2 strongly decreases BCL-xS-induced apoptosis. Reciprocal co-immunoprecipitation, Bak knockdown, VDAC2 overexpression, apoptosis assays Cell Death and Differentiation Medium 22705850
2014 Prior to an apoptotic stimulus, a proportion of BAX that constitutively resides at mitochondria associates with VDAC2. During apoptosis, BAX dissociates from VDAC2 and homo-oligomerizes. In VDAC2-deficient cells, constitutive mitochondrial localization of both BAX and BAK is impaired. BAX requires either VDAC2 or BAK to translocate to and oligomerize at the mitochondrial outer membrane to efficiently mediate apoptosis. BAK homo-oligomerization and pro-apoptotic function requires neither VDAC2 nor BAX. Blue native-PAGE, VDAC2 knockout cells, BAK/VDAC2 silencing epistasis, apoptosis assays Cell Death and Differentiation High 25146925
2014 StAR interacts with VDAC2 at the mitochondria-associated endoplasmic reticulum membrane (MAM) prior to its translocation to the mitochondrial matrix. VDAC2 interacts with StAR via StAR's C-terminal 20 amino acids and N-terminal amino acids 221-229. In the absence of VDAC2, StAR cannot be processed into the mature 30-kDa form, cannot enter mitochondria, and steroidogenesis is inhibited. Tom22 knockdown had no effect on pregnenolone synthesis, establishing isoform specificity. Co-immunoprecipitation, siRNA knockdown, domain mutagenesis, mitochondrial fractionation, steroidogenesis assays Journal of Biological Chemistry High 25505173
2014 GSK-3β translocates from the cytosol to mitochondria in a kinase activity-dependent and VDAC2-specific manner under oxidative stress. VDAC2 was identified as a GSK-3β binding partner by 2D gel electrophoresis and MALDI-TOF/MS. Knockdown of VDAC2 (but not VDAC1 or VDAC3) attenuates both GSK-3β mitochondrial translocation and mitochondrial permeability transition pore (mPTP) opening. The N-terminal Lys-15 residue of GSK-3β is required for mitochondrial translocation. 2D gel electrophoresis, MALDI-TOF/MS, co-immunoprecipitation, siRNA knockdown, time-lapse imaging of GFP-tagged GSK-3β, site-directed mutagenesis Journal of Biological Chemistry High 25187518
2015 VDAC2 interacts with BECN1 and BCL2L1, forming a complex that stabilizes the BECN1-BCL2L1 interaction and suppresses autophagy in the developing ovary. VDAC2 transgenic pigs show inhibited ovarian autophagy, while Vdac2 knockout promotes autophagy. The transcription factors GATA1 and MYBL2 bind to and activate the Vdac2 promoter, and MYBL2 regulates VDAC2 spatiotemporal expression. Transgenic pig overexpression, Vdac2 knockout, co-immunoprecipitation (VDAC2-BECN1-BCL2L1 complex), promoter binding assays, autophagy assays Autophagy Medium 26060891
2015 The N-terminal extension (NTE, 11 extra residues unique to VDAC2) influences chaperone-independent refolding kinetics and thermodynamic stability. The N-terminal helix is crucial for channel activity, while NTE sensitizes VDAC2 to voltage gating. Cysteines and the N-helix have interdependent contributions to channel function and stability. Electrophysiology, site-directed mutagenesis, in vitro refolding assays, thermodynamic stability measurements Journal of Biological Chemistry Medium 26487717
2016 VDAC2 is an essential component and platform for BAX retrotranslocation from mitochondria to the cytosol. In the absence of VDAC2, BAX localizes to other cellular compartments rather than specifically to mitochondria. VDAC2 ensures mitochondria-specific membrane association of BAX and is required for BAX retrotranslocation back to the cytosol (regulated by pro-survival BCL-2 proteins). VDAC2 knockout cells, BAX retrotranslocation assay with isolated mitochondria, subcellular fractionation, fluorescence microscopy Scientific Reports Medium 27620692
2016 VDAC2 loss shifts BAK localization from mitochondria to peroxisomes, resulting in peroxisomal membrane permeabilization and defective peroxisomal biogenesis. Knockdown of BAK or overexpression of BCL-XL or MCL-1 (BAK inhibitors) restores peroxisomal biogenesis in VDAC2-deficient cells. Peroxisome-targeted BAK causes release of peroxisomal matrix proteins to the cytosol. BAK activators PUMA and BIM permeabilize peroxisomes in a BAK-dependent manner. Functional screening, VDAC2 knockout cells, BAK knockdown, overexpression of targeted BAK, peroxisomal fractionation Journal of Cell Biology High 28174205
2017 VDAC2 interacts with PFKP (platelet-type phosphofructokinase) at the mitochondrial membrane and inhibits PFKP-mediated glycolysis. Disruption of VDAC2 induces dedifferentiation of glioma non-stem tumor cells toward a glioma stem cell phenotype with enhanced glycolysis. Enforced VDAC2 expression impairs glioma stem cell self-renewal. PFK inhibitor clotrimazole abolishes the effect of VDAC2 disruption on glycolytic reprogramming. Co-immunoprecipitation, siRNA knockdown, VDAC2 overexpression, glycolysis assays, sphere formation assays Cell Death & Disease Medium 30250190
2018 Genome-wide CRISPR/Cas9 screen identified VDAC2 as specifically required for BAX (but not BAK) apoptotic function. Genetic deletion of VDAC2 abrogated association of both BAX and BAK with mitochondrial complexes containing VDAC1, VDAC2, and VDAC3, but only inhibited BAX apoptotic function. VDAC2 deletion phenocopied BAX loss in impairing tumor cell killing and tumor suppression. Genome-wide CRISPR/Cas9 screen, VDAC2 genetic deletion, blue native-PAGE complex analysis, in vitro killing assays, in vivo tumor formation assays Nature Communications High 30478310
2019 Ceramides bind directly to VDAC2 (and VDAC1) at a ceramide binding site on the barrel wall, mediated by a membrane-buried glutamate residue. Substitution or chemical modification of this glutamate abolishes photolabeling. Unlike VDAC1 loss, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis, establishing VDAC2 as the direct effector of ceramide-mediated cell death. Photoactivatable ceramide probe crosslinking, coarse-grain molecular dynamics simulations, site-directed mutagenesis (E→Q), VDAC2 knockout/knockdown, cell death assays Nature Communications High 31015432
2019 WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit mouse BAK-driven apoptosis. WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential, demonstrating that the VDAC2-BAK interaction interface is pharmacologically tractable. Small molecule binding assay, apoptosis assays, clonogenic survival assays, mouse BAK-specific functional readouts Nature Chemical Biology Medium 31591564
2019 The Noxa extended mitochondrial targeting domain (eMTD) peptide induces necrotic cell death through direct interaction with VDAC2. The eMTD domain binds VDACs and opens the mitochondrial permeability transition pore (mPTP) in a CypD-independent manner. Downregulation of VDAC2 or use of the VDAC inhibitor DIDS inhibits eMTD-induced mPTP opening. Co-immunoprecipitation, siRNA knockdown of VDAC2, DIDS inhibition, mPTP opening assays, cell death assays Cell Death & Disease Medium 31285435
2020 Nedd4 E3 ubiquitin ligase ubiquitinates VDAC2 (and VDAC3) following erastin treatment, leading to their degradation. Erastin binds to VDAC2 and VDAC3. Depletion of Nedd4 limits VDAC2/3 protein degradation and increases cancer cell sensitivity to erastin-induced ferroptosis. A FOXM1-Nedd4-VDAC2/3 negative feedback loop mediates erastin-induced resistance. Ubiquitination assays, co-immunoprecipitation, Nedd4 knockdown/overexpression, ferroptosis assays, protein stability experiments Nature Communications High 31974380
2020 STING binds to VDAC2 at the mitochondrial outer membrane, and this interaction requires STING palmitoylation at C88/C91. STING depletion enhances VDAC2/GRP75-mediated mitochondria-ER contact (MERC) formation, increasing mitochondrial ROS/calcium levels and impairing mTORC1/S6K signaling. Inhibiting STING palmitoylation with 2-BP impedes RCC cell growth. Co-immunoprecipitation, STING depletion, palmitoylation inhibitor (2-BP), mitochondrial ROS/calcium measurements, mTORC1/S6K signaling assays Advanced Science Medium 36445063
2020 IFIT3 directly interacts with VDAC2 and stabilizes its interaction with O-GlcNAc transferase, promoting O-GlcNAcylation of VDAC2. Increased O-GlcNAcylation of VDAC2 protects pancreatic cancer cells from chemotherapy-induced apoptosis. Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assays, IFIT3 knockdown/overexpression, chemotherapy sensitivity assays Theranostics Medium 32641986
2020 Palmitoylated CKAP4 (at Cys100) binds VDAC2 at ER-mitochondria contact sites. CKAP4 knockout enhances IP3R-VDAC2 binding, increases intramitochondrial Ca2+ concentration, and decreases mitochondrial membrane potential. A palmitoylation-deficient CKAP4 mutant cannot rescue these phenotypes. Co-immunoprecipitation, CKAP4 knockout, palmitoylation site mutagenesis (C100A), Ca2+ imaging, mitochondrial membrane potential assays Journal of Cell Science Medium 33067255
2023 VDAC2 lysine 46 (K46) malonylation (driven by elevated malonyl-CoA) alters the N-terminus structure of VDAC2, causing mitochondrial dysfunction, increased mitochondrial ROS, and ferroptosis in cardiomyocytes during sepsis. K46E and K46Q mutations affect malonylation-dependent mitochondrial ferroptosis. Inhibition of malonyl-CoA production (ND-630 or ACC2 knockdown) reduces VDAC2 malonylation and ferroptosis. Mass spectrometry (malonylation site identification), site-directed mutagenesis (K46E/K46Q), molecular dynamics simulation, circular dichroism, siRNA knockdown, mitochondrial ROS assays, ferroptosis assays International Journal of Biological Sciences Medium 37416771
2023 VDAC2 interacts with PI3K and tethers Ras-PI3K-positive endosomes to mitochondria in response to EGF stimulation. VDAC2-mediated mitochondrion-endosome association promotes clathrin-independent endocytosis and endosome maturation. An optogenetics system to force mitochondrion-endosome association confirmed that VDAC2 is functionally implicated in endosome maturation at membrane contact sites. Co-immunoprecipitation (VDAC2-PI3K), optogenetic induction of mitochondrion-endosome association, endocytosis assays, endosome maturation assays Cell Reports Medium 36906852
2024 Deep scanning mutagenesis coupled with cysteine linkage identified key residues at the BAK-VDAC2 interaction interface. Obstructive labeling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupts the VDAC2-BAK interaction. Mutating specific residues in a cytosol-exposed region of VDAC2 stabilizes the interaction with BAK and inhibits BAK apoptotic activity. Deep scanning mutagenesis, cysteine crosslinking, apoptosis assays, interaction assays PLoS Biology High 38696533
2024 TRIM8 E3 ubiquitin ligase interacts with VDAC2, promotes its polyubiquitination and subsequent proteasomal degradation. TRIM8-mediated VDAC2 degradation increases resistance to ferroptosis in ovarian cancer cells. VDAC2 overexpression rescues the ovarian cancer-promoting effects of TRIM8 overexpression. Co-immunoprecipitation, mass spectrometry, ubiquitination assays, TRIM8 knockdown/overexpression, ferroptosis assays Cancer Medicine Medium 38881325
2025 VDAC2 functions as an immune checkpoint that curtails IFNγ-mediated tumor destruction. VDAC2 deficiency enables uncontrolled IFNγ-induced BAK activation and mitochondrial damage, causing aberrant release of mitochondrial DNA into the cytosol and robust cGAS-STING activation. Genome-scale genetic interaction screen identified BAK as the mediator of VDAC2-deficiency effects. Co-deletion of STING pathway components dampens the therapeutic effects of VDAC2 depletion. In vivo and in vitro CRISPR-Cas9 genetic screens, genome-scale genetic interaction screen, BAK knockout epistasis, cGAS-STING pathway assays, IFNγ signaling assays, mitochondrial DNA release assays Nature High 40108474
2025 Scarcity of VDAC2 (and consequent lack of BAK recruitment to mitochondria) renders normal hepatocyte mitochondria resistant to tBID-induced permeabilization. Increased VDAC2 and BAK are found in most human liver cancers, and hepatic cancer cell mitochondria exhibit VDAC2- and BAK-dependent tBID sensitivity. Combinations of tBID pathway activators with BCL-2 inhibitors enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. VDAC2 expression analysis, mitochondrial permeabilization assays, genetic deletion, in vivo tumor models, pharmacological combination experiments Nature Communications Medium 40069152
2011 Human VDAC2 can be reconstituted in functional form in LDAO detergent micelles and DMPC lipid bilayer nanodiscs, and is amenable to structural characterization by solution NMR spectroscopy in both membrane-mimicking systems. Protein reconstitution in detergent micelles and nanodiscs, solution NMR spectroscopy Biochimica et Biophysica Acta Medium 22119777
2014 Solid-state NMR, electrophysiology, and molecular dynamics simulations show that hVDAC2 structure is similar to hVDAC1 in a lipid bilayer environment, but hVDAC2 exhibits increased conformational heterogeneity compared to hVDAC1, reflected in broader NMR spectra and less defined electrophysiological profiles. Solid-state NMR, electrophysiology (planar lipid bilayer), molecular dynamics simulations Journal of Biomolecular NMR Medium 25399320
2009 VDAC2 purified from bovine spermatozoa reconstituted into planar lipid bilayers forms channels with a predominant conductance of ~3.5 nS in 1 M KCl, is anion selective, and shows voltage dependence — confirming it is a functional porin with typical mitochondrial porin electrophysiological characteristics. Protein purification from bovine spermatozoa, planar lipid bilayer electrophysiology reconstitution, 2D electrophoresis, MS peptide sequencing Bioscience Reports Medium 18976238
2023 Celastrol (Cel) directly binds to cysteine residues of VDAC2, identified by chemical proteomics. Binding disrupts VDAC2-mediated mitochondrial permeability transition pore (mPTP) function, inducing cytochrome C release, ROS-mediated ferroptosis, and apoptosis in hepatocellular carcinoma cells. Chemical proteomics (activity-based protein profiling), co-immunoprecipitation, cytochrome C release assays, ROS assays, ferroptosis assays Asian Journal of Pharmaceutical Sciences Medium 38149060
2024 ATF4 transcriptionally regulates vdac2 expression by binding to its promoter (identified by ChIP assay). DBP exposure activates ATF4, upregulates VDAC2, promotes VDAC2 oligomerization, mediates mitochondrial iron influx via VDAC2, and triggers mitochondria-dependent ferroptosis. ChIP assay (ATF4-VDAC2 promoter binding), siRNA knockdown, VDAC2 oligomerization assays, mitochondrial iron influx measurement Environmental Pollution Low 38548160
2024 In rat VDAC2, intramolecular disulfide bridges were identified by high-resolution mass spectrometry, including bridges linking Cys4-Cys5, Cys9-Cys14, alternative bridges between Cys48/Cys77/Cys104, and a highly reduction-resistant bridge between Cys134-Cys139. These disulfide bond patterns are structurally unique features of VDAC2. nanoUHPLC/High-Resolution nanoESI-MS/MS, enzymatic digestion under acidic/neutral pH to prevent disulfide interchange Journal of the American Society for Mass Spectrometry Medium 38832804
2018 Post-translational modifications of VDAC2 cysteines in rat liver mitochondria include over-oxidation (sulfinylation/sulfonylation) and succination. Cysteine over-oxidation appears to be an exclusive feature of VDACs not found in other transmembrane mitochondrial proteins, suggesting regulatory roles for these modifications. Tryptic and chymotryptic proteolysis, UHPLC/High Resolution ESI-MS/MS Biochimica et Biophysica Acta Bioenergetics Low 29890122
2016 Tryptophan residues at specific positions in hVDAC2 control structural integrity and channel function. Mutation of Trp-75, Trp-86, and Trp-221 affects voltage gating characteristics. Trp-160 and Trp-221 are crucial for folding, and the C-terminus to N-terminus directional folding pathway of hVDAC2 was defined. Site-directed mutagenesis of tryptophan residues, electrophysiology, biophysical stability measurements, molecular dynamics simulations Biochimica et Biophysica Acta Medium 27641490
2024 USP18 interacts with VDAC2 and inhibits its ubiquitination and degradation, thereby stabilizing VDAC2 protein. miR-4769-3p targets USP18 to reduce its expression, leading to decreased VDAC2 levels and suppressed adipogenesis in systemic sclerosis. Co-immunoprecipitation (USP18-VDAC2), ubiquitination assays, siRNA knockdown, miRNA functional assays iScience Low 39156653
2025 PDK4-driven glycolysis-dependent lactate accumulation promotes VDAC2 lactylation at lysine 75 (K75). VDAC2 K75 lactylation disrupts its interaction with NBR1, suppressing cardiomyocyte autophagy and exacerbating myocardial injury in septic cardiomyopathy. Metabolomics, proteomics, site-directed mutagenesis (K75), co-immunoprecipitation (VDAC2-NBR1), autophagy assays, murine sepsis model bioRxiv (preprint)preprint Low
2024 Hexokinase I (HKI) directly binds to a charged membrane-buried glutamate on the outer wall of VDAC2 (and VDAC1). The N-terminal α-helix of HKI contacts this glutamate. Protonation of this residue (by cytosolic acidification) causes reversible release of HKI from mitochondria. Membrane thinning at the interaction site facilitates HKI binding. Computer simulations (molecular docking/MD), cell-based acidification experiments, site-directed mutagenesis (VDAC1 membrane-thinning mutant), HKI localization assays bioRxiv (preprint)preprint Low
2024 VDAC2 displays dynamic switching between a few high-conductive anion-selective substates (unlike VDAC1 and VDAC3 which have a unique open state). α-synuclein interacts with all VDAC2 substates but with up to 10-fold different on-rates and blockage times, while maintaining the same equilibrium binding constant. The N-terminal 11-residue extension (NTE) and cysteines contribute to this conformational plasticity. Single-molecule electrophysiology, recombinant hVDAC2 WT and mutants (cysteine-less, NTE-truncated, E84A), α-synuclein as molecular probe bioRxiv (preprint)preprint Low
2024 A small molecule WEHI-3773 inhibits the interaction between VDAC2 and both BAK and BAX through a common interface. Disrupting VDAC2-BAX interaction inhibits BAX-mediated apoptosis by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, disrupting VDAC2-BAK interaction primes BAK for apoptosis by releasing it from inhibitory sequestration. In cells expressing both, WEHI-3773 promotes apoptosis because activated BAK further activates BAX via a feed-forward mechanism. Small molecule VDAC2-BAK/BAX interaction inhibitor, BAX/BAK-specific apoptosis assays, mitochondrial recruitment assays, leukemia models with venetoclax resistance bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science (New York, N.Y.) 683 12881569
2020 Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma. Nature communications 391 31974380
2019 Ceramides bind VDAC2 to trigger mitochondrial apoptosis. Nature communications 188 31015432
2018 VDAC2 enables BAX to mediate apoptosis and limit tumor development. Nature communications 152 30478310
2014 Mitochondria-associated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)-voltage-dependent anion channel 2 (VDAC2) interaction. The Journal of biological chemistry 140 25505173
2009 VDAC2 is required for truncated BID-induced mitochondrial apoptosis by recruiting BAK to the mitochondria. EMBO reports 112 19820692
2001 Changes of voltage-dependent anion-selective channel proteins VDAC1 and VDAC2 brain levels in patients with Alzheimer's disease and Down syndrome. Electrophoresis 112 11197169
2014 Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: a requirement for VDAC2 or Bak for efficient Bax apoptotic function. Cell death and differentiation 111 25146925
2016 VDAC2-specific cellular functions and the underlying structure. Biochimica et biophysica acta 102 27116927
2004 Voltage-dependent anion-selective channels VDAC2 and VDAC3 are abundant proteins in bovine outer dense fibers, a cytoskeletal component of the sperm flagellum. The Journal of biological chemistry 96 14739283
2010 Inhibition of Bak activation by VDAC2 is dependent on the Bak transmembrane anchor. The Journal of biological chemistry 85 20851889
2014 Translocation of glycogen synthase kinase-3β (GSK-3β), a trigger of permeability transition, is kinase activity-dependent and mediated by interaction with voltage-dependent anion channel 2 (VDAC2). The Journal of biological chemistry 79 25187518
2015 MYBL2 guides autophagy suppressor VDAC2 in the developing ovary to inhibit autophagy through a complex of VDAC2-BECN1-BCL2L1 in mammals. Autophagy 78 26060891
2006 VDAC1, having a shorter N-terminus than VDAC2 but showing the same migration in an SDS-polyacrylamide gel, is the predominant form expressed in mitochondria of various tissues. Journal of proteome research 74 17137335
2016 The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation. Scientific reports 71 27620692
2022 Hedyotis diffusa injection induces ferroptosis via the Bax/Bcl2/VDAC2/3 axis in lung adenocarcinoma. Phytomedicine : international journal of phytotherapy and phytopharmacology 60 35853302
2018 VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells. Cell death & disease 59 30250190
2004 All three isoforms of the voltage-dependent anion channel (VDAC1, VDAC2, and VDAC3) are present in mitochondria from bovine, rabbit, and rat brain. Archives of biochemistry and biophysics 58 14759607
2021 VDAC2 and the BCL-2 family of proteins. Biochemical Society transactions 56 34913469
2022 STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 55 36445063
2023 VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis. International journal of biological sciences 54 37416771
2017 The VDAC2-BAK axis regulates peroxisomal membrane permeability. The Journal of cell biology 54 28174205
2009 Molecular and functional characterization of VDAC2 purified from mammal spermatozoa. Bioscience reports 54 18976238
2020 Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics 53 32641986
2015 The association of receptor of activated protein kinase C 1(RACK1) with infectious bursal disease virus viral protein VP5 and voltage-dependent anion channel 2 (VDAC2) inhibits apoptosis and enhances viral replication. The Journal of biological chemistry 52 25583988
2012 Disruption of the VDAC2-Bak interaction by Bcl-x(S) mediates efficient induction of apoptosis in melanoma cells. Cell death and differentiation 52 22705850
2009 The VDAC2-BAK rheostat controls thymocyte survival. Science signaling 50 19706873
2011 Solution NMR spectroscopic characterization of human VDAC-2 in detergent micelles and lipid bilayer nanodiscs. Biochimica et biophysica acta 47 22119777
2025 VDAC2 loss elicits tumour destruction and inflammation for cancer therapy. Nature 46 40108474
2023 Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma. Asian journal of pharmaceutical sciences 46 38149060
2001 VDAC2 (porin-2) expression pattern and localization in the bovine testis. Biochimica et biophysica acta 44 11311949
2019 A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis. Nature chemical biology 37 31591564
2020 Palmitoylated CKAP4 regulates mitochondrial functions through an interaction with VDAC2 at ER-mitochondria contact sites. Journal of cell science 36 33067255
2018 Post-translational modifications of VDAC1 and VDAC2 cysteines from rat liver mitochondria. Biochimica et biophysica acta. Bioenergetics 33 29890122
2016 VDAC-2: Mitochondrial outer membrane regulator masquerading as a channel? The FEBS journal 33 26709731
2007 Analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced proteome changes in 5L rat hepatoma cells reveals novel targets of dioxin action including the mitochondrial apoptosis regulator VDAC2. Molecular & cellular proteomics : MCP 33 17998243
2016 Mitochondrial VDAC2 and cell homeostasis: highlighting hidden structural features and unique functionalities. Biological reviews of the Cambridge Philosophical Society 31 28980434
2015 N-helix and Cysteines Inter-regulate Human Mitochondrial VDAC-2 Function and Biochemistry. The Journal of biological chemistry 30 26487717
2014 Solid-state NMR, electrophysiology and molecular dynamics characterization of human VDAC2. Journal of biomolecular NMR 27 25399320
2019 Voltage-Dependent Anion Channel Protein 2 (VDAC2) and Receptor of Activated Protein C Kinase 1 (RACK1) Act as Functional Receptors for Lymphocystis Disease Virus Infection. Journal of virology 24 30918079
2016 Abnormal Hypermethylation of the VDAC2 Promoter is a Potential Cause of Idiopathic Asthenospermia in Men. Scientific reports 22 27892527
2018 Hydrophobic Mismatch Modulates Stability and Plasticity of Human Mitochondrial VDAC2. Biophysical journal 20 30503532
2014 Influence of protein-micelle ratios and cysteine residues on the kinetic stability and unfolding rates of human mitochondrial VDAC-2. PloS one 19 24494036
2020 Downregulation of vdac2 inhibits spermatogenesis via JNK and P53 signalling in mice exposed to cadmium. Toxicology letters 18 32199951
2019 Noxa mitochondrial targeting domain induces necrosis via VDAC2 and mitochondrial catastrophe. Cell death & disease 17 31285435
2016 Characterization of Oyster Voltage-Dependent Anion Channel 2 (VDAC2) Suggests Its Involvement in Apoptosis and Host Defense. PloS one 17 26727366
2013 Structural insights into proapoptotic signaling mediated by MTCH2, VDAC2, TOM40 and TOM22. Cellular signalling 17 24269536
2023 Interaction between PI3K and the VDAC2 channel tethers Ras-PI3K-positive endosomes to mitochondria and promotes endosome maturation. Cell reports 16 36906852
2020 Structure-based modeling of turnover of Bcl-2 family proteins bound to voltage-dependent anion channel 2 (VDAC2): Implications for the mechanisms of proapoptotic activation of Bak and Bax in vivo. Computational biology and chemistry 16 31981967
2019 Structural characterization of the human membrane protein VDAC2 in lipid bilayers by MAS NMR. Journal of biomolecular NMR 16 31407201
2024 Dibutyl phthalate exposure induced mitochondria-dependent ferroptosis by enhancing VDAC2 in zebrafish ZF4 cells. Environmental pollution (Barking, Essex : 1987) 13 38548160
2008 VDAC2 and aldolase A identified as membrane proteins of K562 cells with increased expression under iron deprivation. Molecular and cellular biochemistry 12 18278581
2019 Recombinant yeast VDAC2: a comparison of electrophysiological features with the native form. FEBS open bio 11 31206247
2025 VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes. Nature communications 8 40069152
2024 Melatonin alleviates di-butyl phthalate (DBP)-induced ferroptosis of mouse leydig cells via inhibiting Sp2/VDAC2 signals. Environmental research 8 38246300
2017 ROS-mediated oligomerization of VDAC2 is associated with quinocetone-induced apoptotic cell death. Toxicology in vitro : an international journal published in association with BIBRA 8 29229420
2016 Control of human VDAC-2 scaffold dynamics by interfacial tryptophans is position specific. Biochimica et biophysica acta 8 27641490
2024 TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation. Cancer medicine 7 38881325
2022 Voltage-dependent anion channel 2 (VDAC2) facilitates the accumulation of rice stripe virus in the vector Laodelphax striatellus. Virus research 7 36496034
2024 Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis. PLoS biology 6 38696533
2023 SH3BP5-AS1/IGF2BP2/VDAC2 Axis Promotes the Apoptosis and Ferroptosis of Bladder Cancer Cells. Bladder cancer (Amsterdam, Netherlands) 5 38994477
2019 Tiger frog virus ORF104R interacts with cellular VDAC2 to inhibit cell apoptosis. Fish & shellfish immunology 5 31299465
2016 Idiopathic male infertility in the Han population in China is affected by polymorphism in the VDAC2 gene. Oncotarget 5 27806320
2015 Tissue distribution of olive flounder VDAC2 and its expression in fish cell lines. Fish physiology and biochemistry 4 25893906
2025 VDAC2 brake release: unleashing inflammation via IFNγ. Trends in pharmacological sciences 3 40738806
2024 GCRV-II major outer capsid protein VP4 promotes cell apoptosis by VDAC2-mediated calcium pathway facilitation. International journal of biological macromolecules 3 39631593
2024 Lamprey VDAC2: Suppressing hydrogen peroxide-induced 293T cell apoptosis by downregulating BAK expression. Fish & shellfish immunology 2 38740227
2024 Intramolecular Disulfide Bridges in Voltage-Dependent Anion Channel 2 (VDAC2) Protein from Rattus norvegicus Revealed by High-Resolution Mass Spectrometry. Journal of the American Society for Mass Spectrometry 2 38832804
2024 MiR-4769-3p suppresses adipogenesis in systemic sclerosis by negatively regulating the USP18/VDAC2 pathway. iScience 2 39156653
2021 Protein mass spectrometry reveals lycorine exerting anti-multiple-myeloma effect by acting on VDAC2 and causing mitochondrial abnormalities. Biotechnology letters 2 33386501
2026 VDAC2: an emerging pivotal and multifaceted regulator in tumor biology. Apoptosis : an international journal on programmed cell death 0 41622340
2026 Perspectives from machine learning and multi-omics to decoding the effects of VDAC2 malignant subsets on tumor evolution. NPJ precision oncology 0 41917254
2026 ZIP14-VDAC2 mediates the transport of extracellular iron into mitochondria in hepatocytes under PFOS exposure. Chemico-biological interactions 0 42036059
2025 Synergetic effect of doxorubicin and avenanthramide C on VDAC2/MTCH1 mitochondrial axis in breast cancer cells. International journal of health sciences 0 40046789
2025 VDAC2 Mediates the Apoptosis of Cashmere Goat Hair Follicle Stem Cells Through the P53 Signaling Pathway. Animals : an open access journal from MDPI 0 40509137
2025 Multi-omics nominates VDAC2 as a candidate protective locus in sepsis-associated cholesterol dysregulation. Apoptosis : an international journal on programmed cell death 0 41109923
2025 SEMA5B depletion suppresses cell proliferation and glycolysis by downregulating VDAC2 expression in esophageal squamous cell carcinoma. International journal of biological macromolecules 0 41407227

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