{"gene":"VDAC2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"Co-immunoprecipitation, VDAC2 knockout MEFs, overexpression studies, apoptosis assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined phenotype, replicated across multiple subsequent labs","pmids":["12881569"],"is_preprint":false},{"year":2009,"finding":"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.","method":"VDAC isoform-specific knockout MEFs, cytochrome c release assays, mitochondrial fractionation, recombinant protein reconstitution","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular phenotype (BAK mislocalization), multiple orthogonal methods, isoform specificity established","pmids":["19820692"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Conditional genetic knockout mice, epistasis analysis (double KO), in vivo thymocyte survival assays","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with double KO rescue, isoform-specific (Bak not Bax), defined phenotype","pmids":["19706873"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Blue native-PAGE, site-directed mutagenesis of BAK transmembrane domain, apoptosis assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — blue native-PAGE complex identification, mutagenesis of BAK tail anchor, functional consequence measured","pmids":["20851889"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Reciprocal co-immunoprecipitation, Bak knockdown, VDAC2 overexpression, apoptosis assays","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional rescue experiments, single lab","pmids":["22705850"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Blue native-PAGE, VDAC2 knockout cells, BAK/VDAC2 silencing epistasis, apoptosis assays","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — blue native-PAGE complex identification, genetic epistasis (VDAC2 KO + BAK silencing), multiple orthogonal methods, replicated findings","pmids":["25146925"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, domain mutagenesis, mitochondrial fractionation, steroidogenesis assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutagenesis, siRNA KD with functional readout (steroidogenesis), multiple orthogonal methods","pmids":["25505173"],"is_preprint":false},{"year":2014,"finding":"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.","method":"2D gel electrophoresis, MALDI-TOF/MS, co-immunoprecipitation, siRNA knockdown, time-lapse imaging of GFP-tagged GSK-3β, site-directed mutagenesis","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS-based interaction identification, isoform-specific siRNA KD with functional readout (mPTP opening), mutagenesis of GSK-3β interaction domain","pmids":["25187518"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Transgenic pig overexpression, Vdac2 knockout, co-immunoprecipitation (VDAC2-BECN1-BCL2L1 complex), promoter binding assays, autophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss-of-function with defined phenotype, Co-IP of complex, promoter binding; single lab","pmids":["26060891"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Electrophysiology, site-directed mutagenesis, in vitro refolding assays, thermodynamic stability measurements","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution and mutagenesis with electrophysiology, single lab","pmids":["26487717"],"is_preprint":false},{"year":2016,"finding":"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).","method":"VDAC2 knockout cells, BAX retrotranslocation assay with isolated mitochondria, subcellular fractionation, fluorescence microscopy","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — VDAC2 KO with defined phenotype (BAX mislocalization), retrotranslocation assay with isolated mitochondria, single lab","pmids":["27620692"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Functional screening, VDAC2 knockout cells, BAK knockdown, overexpression of targeted BAK, peroxisomal fractionation","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue experiments, multiple orthogonal approaches, novel cellular function (peroxisomal permeability) established via VDAC2-BAK axis","pmids":["28174205"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, VDAC2 overexpression, glycolysis assays, sphere formation assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of VDAC2-PFKP interaction, loss/gain-of-function with metabolic phenotype, pharmacological rescue; single lab","pmids":["30250190"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Genome-wide CRISPR/Cas9 screen, VDAC2 genetic deletion, blue native-PAGE complex analysis, in vitro killing assays, in vivo tumor formation assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide screen plus genetic deletion with multiple phenotypic readouts including in vivo, complex analysis by blue native-PAGE","pmids":["30478310"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Photoactivatable ceramide probe crosslinking, coarse-grain molecular dynamics simulations, site-directed mutagenesis (E→Q), VDAC2 knockout/knockdown, cell death assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — photocrosslinking identification, mutagenesis abolishing binding, KO with functional rescue, MD simulations; multiple orthogonal methods","pmids":["31015432"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Small molecule binding assay, apoptosis assays, clonogenic survival assays, mouse BAK-specific functional readouts","journal":"Nature Chemical Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — small molecule-VDAC2 binding identified, functional apoptosis inhibition demonstrated; single lab, mechanism partially defined","pmids":["31591564"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown of VDAC2, DIDS inhibition, mPTP opening assays, cell death assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, VDAC2-specific KD with functional rescue, pharmacological inhibition; single lab","pmids":["31285435"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Ubiquitination assays, co-immunoprecipitation, Nedd4 knockdown/overexpression, ferroptosis assays, protein stability experiments","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ubiquitination assay identifying Nedd4 as E3 ligase for VDAC2, KD functional rescue, feedback loop established; multiple orthogonal methods","pmids":["31974380"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, STING depletion, palmitoylation inhibitor (2-BP), mitochondrial ROS/calcium measurements, mTORC1/S6K signaling assays","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying STING-VDAC2 interaction, palmitoylation requirement demonstrated, functional consequences measured; single lab","pmids":["36445063"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assays, IFIT3 knockdown/overexpression, chemotherapy sensitivity assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction, post-translational modification (O-GlcNAcylation) characterized, functional consequence established; single lab","pmids":["32641986"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, CKAP4 knockout, palmitoylation site mutagenesis (C100A), Ca2+ imaging, mitochondrial membrane potential assays","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined phenotype, palmitoylation mutagenesis functionally validated, interaction identified; single lab","pmids":["33067255"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Mass spectrometry (malonylation site identification), site-directed mutagenesis (K46E/K46Q), molecular dynamics simulation, circular dichroism, siRNA knockdown, mitochondrial ROS assays, ferroptosis assays","journal":"International Journal of Biological Sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS-identified PTM, mutagenesis, MD simulation, functional rescue; single lab","pmids":["37416771"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation (VDAC2-PI3K), optogenetic induction of mitochondrion-endosome association, endocytosis assays, endosome maturation assays","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, optogenetics-based organelle contact manipulation, functional assays; single lab","pmids":["36906852"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Deep scanning mutagenesis, cysteine crosslinking, apoptosis assays, interaction assays","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — deep mutagenesis with cysteine crosslinking defining precise interaction interface, functional consequences; single lab but rigorous methods","pmids":["38696533"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, TRIM8 knockdown/overexpression, ferroptosis assays","journal":"Cancer Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay identifying TRIM8 as E3 ligase, functional rescue; single lab","pmids":["38881325"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual genetic screens, epistasis (BAK KO rescue), mechanistic pathway (VDAC2-BAK-mtDNA-cGAS-STING) established with multiple orthogonal methods in vivo and in vitro","pmids":["40108474"],"is_preprint":false},{"year":2025,"finding":"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.","method":"VDAC2 expression analysis, mitochondrial permeabilization assays, genetic deletion, in vivo tumor models, pharmacological combination experiments","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological experiments establishing VDAC2-BAK axis in tissue-specific context; mechanistic follow-up of established pathway","pmids":["40069152"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Protein reconstitution in detergent micelles and nanodiscs, solution NMR spectroscopy","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with NMR characterization, single lab, limited functional validation","pmids":["22119777"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Solid-state NMR, electrophysiology (planar lipid bilayer), molecular dynamics simulations","journal":"Journal of Biomolecular NMR","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — multidisciplinary structural study with electrophysiology; single lab, limited functional consequence established","pmids":["25399320"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Protein purification from bovine spermatozoa, planar lipid bilayer electrophysiology reconstitution, 2D electrophoresis, MS peptide sequencing","journal":"Bioscience Reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with electrophysiology from native tissue purification; first characterization of VDAC2 channel activity from mammalian tissue, single lab","pmids":["18976238"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Chemical proteomics (activity-based protein profiling), co-immunoprecipitation, cytochrome C release assays, ROS assays, ferroptosis assays","journal":"Asian Journal of Pharmaceutical Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical proteomics-based target identification, functional consequences established; single lab","pmids":["38149060"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP assay (ATF4-VDAC2 promoter binding), siRNA knockdown, VDAC2 oligomerization assays, mitochondrial iron influx measurement","journal":"Environmental Pollution","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP for transcriptional regulation, functional assays for VDAC2-mediated iron influx; single lab, limited mechanistic depth on VDAC2 itself","pmids":["38548160"],"is_preprint":false},{"year":2024,"finding":"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.","method":"nanoUHPLC/High-Resolution nanoESI-MS/MS, enzymatic digestion under acidic/neutral pH to prevent disulfide interchange","journal":"Journal of the American Society for Mass Spectrometry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous MS-based structural characterization; single lab, functional consequences of specific disulfide bonds not tested","pmids":["38832804"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Tryptic and chymotryptic proteolysis, UHPLC/High Resolution ESI-MS/MS","journal":"Biochimica et Biophysica Acta Bioenergetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MS-based PTM characterization from native tissue; functional roles of specific modifications not directly tested","pmids":["29890122"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Site-directed mutagenesis of tryptophan residues, electrophysiology, biophysical stability measurements, molecular dynamics simulations","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with electrophysiology and biophysical characterization; single lab","pmids":["27641490"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation (USP18-VDAC2), ubiquitination assays, siRNA knockdown, miRNA functional assays","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP identifying deubiquitinase interaction, limited direct mechanistic characterization of VDAC2; single lab","pmids":["39156653"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Metabolomics, proteomics, site-directed mutagenesis (K75), co-immunoprecipitation (VDAC2-NBR1), autophagy assays, murine sepsis model","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 2 / Weak — mutagenesis and Co-IP identifying lactylation-disrupted interaction; preprint, single lab, not peer-reviewed","pmids":[],"is_preprint":true},{"year":2024,"finding":"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.","method":"Computer simulations (molecular docking/MD), cell-based acidification experiments, site-directed mutagenesis (VDAC1 membrane-thinning mutant), HKI localization assays","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, primarily computational with limited cell experiments; mutagenesis done on VDAC1 not VDAC2 specifically","pmids":[],"is_preprint":true},{"year":2024,"finding":"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.","method":"Single-molecule electrophysiology, recombinant hVDAC2 WT and mutants (cysteine-less, NTE-truncated, E84A), α-synuclein as molecular probe","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 1 / Weak — rigorous single-molecule electrophysiology with multiple mutants; preprint not yet peer-reviewed, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"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.","method":"Small molecule VDAC2-BAK/BAX interaction inhibitor, BAX/BAK-specific apoptosis assays, mitochondrial recruitment assays, leukemia models with venetoclax resistance","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, pharmacological tool to dissect interaction, functional assays; not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"VDAC2 is a mitochondrial outer membrane β-barrel channel that serves as a critical isoform-specific regulator of apoptosis, acting as a platform that recruits and sequesters BAK in an inactive state (via its transmembrane anchor) and facilitates BAX targeting to mitochondria and retrotranslocation; death signals (tBID, BIM, BH3-only proteins) or small molecules displace VDAC2 from BAK to trigger apoptosis, while VDAC2 is itself regulated by post-translational modifications including ubiquitination (by Nedd4 and TRIM8, promoting degradation), O-GlcNAcylation (by OGT stabilized by IFIT3), malonylation (at K46, promoting ferroptosis), and lactylation (at K75, impairing autophagy); VDAC2 also directly binds ceramides at a membrane-buried glutamate to mediate ceramide-induced apoptosis, interacts with StAR to control steroidogenesis at MAMs, interacts with GSK-3β to mediate its mitochondrial translocation and mPTP opening, binds PFKP to regulate glycolysis, and acts as an innate immune checkpoint by restraining BAK-mediated IFNγ-induced mtDNA release and cGAS-STING activation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["12881569"],"confidence":"High","gaps":["Structural basis of the VDAC2–BAK contact not resolved","Whether channel conductance contributes to sequestration untested"]},{"year":2009,"claim":"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","pmids":["19820692","19706873"],"confidence":"High","gaps":["Mechanism of mitochondrial targeting via VDAC2 not defined","Does not address BAX recruitment"]},{"year":2010,"claim":"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","pmids":["20851889"],"confidence":"High","gaps":["Other complex components beyond VDAC2 not identified","No atomic-resolution interface"]},{"year":2012,"claim":"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","pmids":["22705850"],"confidence":"Medium","gaps":["Single lab","Direct competition for the same VDAC2 surface not structurally demonstrated"]},{"year":2014,"claim":"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","pmids":["25146925","25505173","25187518"],"confidence":"High","gaps":["How VDAC2 discriminates BAX from BAK regulation unresolved","Channel function versus scaffolding contribution not separated"]},{"year":2016,"claim":"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","pmids":["27620692","28174205"],"confidence":"High","gaps":["Determinants of organelle targeting selectivity unknown","Mechanism of retrotranslocation not reconstituted"]},{"year":2017,"claim":"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","pmids":["30250190"],"confidence":"Medium","gaps":["Single lab","Whether channel activity is required for PFKP regulation untested"]},{"year":2018,"claim":"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","pmids":["30478310"],"confidence":"High","gaps":["Reconciliation with BAK-sequestration role context-dependent","Structural basis of differential effector handling open"]},{"year":2019,"claim":"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","pmids":["31015432","31591564","31285435"],"confidence":"High","gaps":["Physiological ceramide pools engaging VDAC2 in vivo unmapped","WEHI-9625 mechanism species-specific (mouse BAK)"]},{"year":2020,"claim":"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","pmids":["31974380","32641986","36445063","33067255"],"confidence":"Medium","gaps":["Modified residues for ubiquitin/O-GlcNAc not all mapped","Crosstalk between distinct PTMs untested"]},{"year":2023,"claim":"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","pmids":["37416771","30250190","38149060","36906852"],"confidence":"Medium","gaps":["Single labs","Direct link between N-terminal structural change and channel gating untested"]},{"year":2024,"claim":"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","pmids":["38696533","38881325","38832804"],"confidence":"High","gaps":["No co-crystal/cryo-EM of the complex","Functional roles of individual disulfides not tested"]},{"year":2025,"claim":"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","pmids":["40108474","40069152"],"confidence":"High","gaps":["How IFNγ tips the VDAC2-BAK balance mechanistically unresolved","Selectivity of therapeutic window across tissues not fully defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[9,28,29,34]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6,10,13]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,3,5]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,20]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,5,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12]}],"complexes":["VDAC2-BAK inactive complex","VDAC2-BECN1-BCL2L1 complex"],"partners":["BAK1","BAX","STAR","GSK3B","PFKP","BECN1","STING1","CKAP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P45880","full_name":"Non-selective voltage-gated ion channel VDAC2","aliases":["Outer mitochondrial membrane protein porin 2"],"length_aa":294,"mass_kda":31.6,"function":"Non-selective voltage-gated ion channel that mediates the transport of anions and cations through the mitochondrion outer membrane and plasma membrane (PubMed:8420959). The channel adopts an open conformation at zero mV and a closed conformation at both positive and negative potentials (PubMed:8420959). There are two populations of channels; the main that functions in a lower open-state conductance with lower ion selectivity, that switch, in a voltage-dependent manner, from the open to a low-conducting 'closed' state and the other that has a normal ion selectivity in the typical high conductance, 'open' state (PubMed:8420959). Binds various lipids, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterols cholesterol and oxysterol (PubMed:31015432). Binding of ceramide promotes the mitochondrial outer membrane permeabilization (MOMP) apoptotic pathway (PubMed:31015432). Associates with the translocase of the outer mitochondrial membrane (TOM) complex and PINK1 kinase at depolarized mitochondria, this interaction stabilizes PINK1 at the outer mitochondrial membrane and triggers downstream mitophagy by the recruitment of the E3 ubiquitin ligase PRKN (PubMed:40080546) Catalyzes the scrambling of phospholipids across the outer mitochondrial membrane; the mechanism is unrelated to channel activity and is capable of translocating both anionic and zwitterionic phospholipids","subcellular_location":"Mitochondrion outer membrane; Membrane","url":"https://www.uniprot.org/uniprotkb/P45880/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VDAC2","classification":"Not 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VDAC1","url":"https://www.omim.org/entry/604492"},{"mim_id":"600516","title":"BCL2 ANTAGONIST KILLER 1; BAK1","url":"https://www.omim.org/entry/600516"},{"mim_id":"193245","title":"VOLTAGE-DEPENDENT ANION CHANNEL 2; VDAC2","url":"https://www.omim.org/entry/193245"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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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.\",\n      \"method\": \"Co-immunoprecipitation, VDAC2 knockout MEFs, overexpression studies, apoptosis assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined phenotype, replicated across multiple subsequent labs\",\n      \"pmids\": [\"12881569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"VDAC isoform-specific knockout MEFs, cytochrome c release assays, mitochondrial fractionation, recombinant protein reconstitution\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular phenotype (BAK mislocalization), multiple orthogonal methods, isoform specificity established\",\n      \"pmids\": [\"19820692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional genetic knockout mice, epistasis analysis (double KO), in vivo thymocyte survival assays\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with double KO rescue, isoform-specific (Bak not Bax), defined phenotype\",\n      \"pmids\": [\"19706873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Blue native-PAGE, site-directed mutagenesis of BAK transmembrane domain, apoptosis assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — blue native-PAGE complex identification, mutagenesis of BAK tail anchor, functional consequence measured\",\n      \"pmids\": [\"20851889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Reciprocal co-immunoprecipitation, Bak knockdown, VDAC2 overexpression, apoptosis assays\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional rescue experiments, single lab\",\n      \"pmids\": [\"22705850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Blue native-PAGE, VDAC2 knockout cells, BAK/VDAC2 silencing epistasis, apoptosis assays\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — blue native-PAGE complex identification, genetic epistasis (VDAC2 KO + BAK silencing), multiple orthogonal methods, replicated findings\",\n      \"pmids\": [\"25146925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, domain mutagenesis, mitochondrial fractionation, steroidogenesis assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutagenesis, siRNA KD with functional readout (steroidogenesis), multiple orthogonal methods\",\n      \"pmids\": [\"25505173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"2D gel electrophoresis, MALDI-TOF/MS, co-immunoprecipitation, siRNA knockdown, time-lapse imaging of GFP-tagged GSK-3β, site-directed mutagenesis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interaction identification, isoform-specific siRNA KD with functional readout (mPTP opening), mutagenesis of GSK-3β interaction domain\",\n      \"pmids\": [\"25187518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Transgenic pig overexpression, Vdac2 knockout, co-immunoprecipitation (VDAC2-BECN1-BCL2L1 complex), promoter binding assays, autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss-of-function with defined phenotype, Co-IP of complex, promoter binding; single lab\",\n      \"pmids\": [\"26060891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology, site-directed mutagenesis, in vitro refolding assays, thermodynamic stability measurements\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution and mutagenesis with electrophysiology, single lab\",\n      \"pmids\": [\"26487717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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).\",\n      \"method\": \"VDAC2 knockout cells, BAX retrotranslocation assay with isolated mitochondria, subcellular fractionation, fluorescence microscopy\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — VDAC2 KO with defined phenotype (BAX mislocalization), retrotranslocation assay with isolated mitochondria, single lab\",\n      \"pmids\": [\"27620692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Functional screening, VDAC2 knockout cells, BAK knockdown, overexpression of targeted BAK, peroxisomal fractionation\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiments, multiple orthogonal approaches, novel cellular function (peroxisomal permeability) established via VDAC2-BAK axis\",\n      \"pmids\": [\"28174205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, VDAC2 overexpression, glycolysis assays, sphere formation assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of VDAC2-PFKP interaction, loss/gain-of-function with metabolic phenotype, pharmacological rescue; single lab\",\n      \"pmids\": [\"30250190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, VDAC2 genetic deletion, blue native-PAGE complex analysis, in vitro killing assays, in vivo tumor formation assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide screen plus genetic deletion with multiple phenotypic readouts including in vivo, complex analysis by blue native-PAGE\",\n      \"pmids\": [\"30478310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Photoactivatable ceramide probe crosslinking, coarse-grain molecular dynamics simulations, site-directed mutagenesis (E→Q), VDAC2 knockout/knockdown, cell death assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — photocrosslinking identification, mutagenesis abolishing binding, KO with functional rescue, MD simulations; multiple orthogonal methods\",\n      \"pmids\": [\"31015432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Small molecule binding assay, apoptosis assays, clonogenic survival assays, mouse BAK-specific functional readouts\",\n      \"journal\": \"Nature Chemical Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — small molecule-VDAC2 binding identified, functional apoptosis inhibition demonstrated; single lab, mechanism partially defined\",\n      \"pmids\": [\"31591564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of VDAC2, DIDS inhibition, mPTP opening assays, cell death assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, VDAC2-specific KD with functional rescue, pharmacological inhibition; single lab\",\n      \"pmids\": [\"31285435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Ubiquitination assays, co-immunoprecipitation, Nedd4 knockdown/overexpression, ferroptosis assays, protein stability experiments\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ubiquitination assay identifying Nedd4 as E3 ligase for VDAC2, KD functional rescue, feedback loop established; multiple orthogonal methods\",\n      \"pmids\": [\"31974380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, STING depletion, palmitoylation inhibitor (2-BP), mitochondrial ROS/calcium measurements, mTORC1/S6K signaling assays\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying STING-VDAC2 interaction, palmitoylation requirement demonstrated, functional consequences measured; single lab\",\n      \"pmids\": [\"36445063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assays, IFIT3 knockdown/overexpression, chemotherapy sensitivity assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction, post-translational modification (O-GlcNAcylation) characterized, functional consequence established; single lab\",\n      \"pmids\": [\"32641986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, CKAP4 knockout, palmitoylation site mutagenesis (C100A), Ca2+ imaging, mitochondrial membrane potential assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined phenotype, palmitoylation mutagenesis functionally validated, interaction identified; single lab\",\n      \"pmids\": [\"33067255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry (malonylation site identification), site-directed mutagenesis (K46E/K46Q), molecular dynamics simulation, circular dichroism, siRNA knockdown, mitochondrial ROS assays, ferroptosis assays\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS-identified PTM, mutagenesis, MD simulation, functional rescue; single lab\",\n      \"pmids\": [\"37416771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (VDAC2-PI3K), optogenetic induction of mitochondrion-endosome association, endocytosis assays, endosome maturation assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, optogenetics-based organelle contact manipulation, functional assays; single lab\",\n      \"pmids\": [\"36906852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Deep scanning mutagenesis, cysteine crosslinking, apoptosis assays, interaction assays\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — deep mutagenesis with cysteine crosslinking defining precise interaction interface, functional consequences; single lab but rigorous methods\",\n      \"pmids\": [\"38696533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, TRIM8 knockdown/overexpression, ferroptosis assays\",\n      \"journal\": \"Cancer Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay identifying TRIM8 as E3 ligase, functional rescue; single lab\",\n      \"pmids\": [\"38881325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual genetic screens, epistasis (BAK KO rescue), mechanistic pathway (VDAC2-BAK-mtDNA-cGAS-STING) established with multiple orthogonal methods in vivo and in vitro\",\n      \"pmids\": [\"40108474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"VDAC2 expression analysis, mitochondrial permeabilization assays, genetic deletion, in vivo tumor models, pharmacological combination experiments\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological experiments establishing VDAC2-BAK axis in tissue-specific context; mechanistic follow-up of established pathway\",\n      \"pmids\": [\"40069152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Protein reconstitution in detergent micelles and nanodiscs, solution NMR spectroscopy\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with NMR characterization, single lab, limited functional validation\",\n      \"pmids\": [\"22119777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Solid-state NMR, electrophysiology (planar lipid bilayer), molecular dynamics simulations\",\n      \"journal\": \"Journal of Biomolecular NMR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — multidisciplinary structural study with electrophysiology; single lab, limited functional consequence established\",\n      \"pmids\": [\"25399320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Protein purification from bovine spermatozoa, planar lipid bilayer electrophysiology reconstitution, 2D electrophoresis, MS peptide sequencing\",\n      \"journal\": \"Bioscience Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with electrophysiology from native tissue purification; first characterization of VDAC2 channel activity from mammalian tissue, single lab\",\n      \"pmids\": [\"18976238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Chemical proteomics (activity-based protein profiling), co-immunoprecipitation, cytochrome C release assays, ROS assays, ferroptosis assays\",\n      \"journal\": \"Asian Journal of Pharmaceutical Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical proteomics-based target identification, functional consequences established; single lab\",\n      \"pmids\": [\"38149060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay (ATF4-VDAC2 promoter binding), siRNA knockdown, VDAC2 oligomerization assays, mitochondrial iron influx measurement\",\n      \"journal\": \"Environmental Pollution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP for transcriptional regulation, functional assays for VDAC2-mediated iron influx; single lab, limited mechanistic depth on VDAC2 itself\",\n      \"pmids\": [\"38548160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"nanoUHPLC/High-Resolution nanoESI-MS/MS, enzymatic digestion under acidic/neutral pH to prevent disulfide interchange\",\n      \"journal\": \"Journal of the American Society for Mass Spectrometry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous MS-based structural characterization; single lab, functional consequences of specific disulfide bonds not tested\",\n      \"pmids\": [\"38832804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Tryptic and chymotryptic proteolysis, UHPLC/High Resolution ESI-MS/MS\",\n      \"journal\": \"Biochimica et Biophysica Acta Bioenergetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MS-based PTM characterization from native tissue; functional roles of specific modifications not directly tested\",\n      \"pmids\": [\"29890122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of tryptophan residues, electrophysiology, biophysical stability measurements, molecular dynamics simulations\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with electrophysiology and biophysical characterization; single lab\",\n      \"pmids\": [\"27641490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (USP18-VDAC2), ubiquitination assays, siRNA knockdown, miRNA functional assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP identifying deubiquitinase interaction, limited direct mechanistic characterization of VDAC2; single lab\",\n      \"pmids\": [\"39156653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Metabolomics, proteomics, site-directed mutagenesis (K75), co-immunoprecipitation (VDAC2-NBR1), autophagy assays, murine sepsis model\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mutagenesis and Co-IP identifying lactylation-disrupted interaction; preprint, single lab, not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Computer simulations (molecular docking/MD), cell-based acidification experiments, site-directed mutagenesis (VDAC1 membrane-thinning mutant), HKI localization assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, primarily computational with limited cell experiments; mutagenesis done on VDAC1 not VDAC2 specifically\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Single-molecule electrophysiology, recombinant hVDAC2 WT and mutants (cysteine-less, NTE-truncated, E84A), α-synuclein as molecular probe\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous single-molecule electrophysiology with multiple mutants; preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Small molecule VDAC2-BAK/BAX interaction inhibitor, BAX/BAK-specific apoptosis assays, mitochondrial recruitment assays, leukemia models with venetoclax resistance\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, pharmacological tool to dissect interaction, functional assays; not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"VDAC2 is a mitochondrial outer membrane β-barrel channel that serves as a critical isoform-specific regulator of apoptosis, acting as a platform that recruits and sequesters BAK in an inactive state (via its transmembrane anchor) and facilitates BAX targeting to mitochondria and retrotranslocation; death signals (tBID, BIM, BH3-only proteins) or small molecules displace VDAC2 from BAK to trigger apoptosis, while VDAC2 is itself regulated by post-translational modifications including ubiquitination (by Nedd4 and TRIM8, promoting degradation), O-GlcNAcylation (by OGT stabilized by IFIT3), malonylation (at K46, promoting ferroptosis), and lactylation (at K75, impairing autophagy); VDAC2 also directly binds ceramides at a membrane-buried glutamate to mediate ceramide-induced apoptosis, interacts with StAR to control steroidogenesis at MAMs, interacts with GSK-3β to mediate its mitochondrial translocation and mPTP opening, binds PFKP to regulate glycolysis, and acts as an innate immune checkpoint by restraining BAK-mediated IFNγ-induced mtDNA release and cGAS-STING activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #13]. 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 [#0, #3, #4]. 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 [#1, #5, #10, #11, #13]. 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 [#15, #23]. 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 [#2, #25, #26]. 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 [#6, #7, #12, #14, #22]. 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 [#17, #19, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, VDAC2-knockout MEFs, overexpression and apoptosis assays showing VDAC2 binds inactive BAK and BH3-only proteins displace it\",\n      \"pmids\": [\"12881569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the VDAC2–BAK contact not resolved\", \"Whether channel conductance contributes to sequestration untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Isoform-specific KO MEFs with cytochrome c release and reconstitution; conditional KO mice with Bak/Bax epistasis\",\n      \"pmids\": [\"19820692\", \"19706873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mitochondrial targeting via VDAC2 not defined\", \"Does not address BAX recruitment\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Blue native-PAGE and BAK transmembrane-domain mutagenesis with apoptosis readouts\",\n      \"pmids\": [\"20851889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other complex components beyond VDAC2 not identified\", \"No atomic-resolution interface\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified BCL-xS as a proapoptotic ligand that works indirectly by displacing BAK from VDAC2, reinforcing the displacement model.\",\n      \"evidence\": \"Reciprocal Co-IP, Bak knockdown and VDAC2 overexpression in melanoma cells\",\n      \"pmids\": [\"22705850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct competition for the same VDAC2 surface not structurally demonstrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"25146925\", \"25505173\", \"25187518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VDAC2 discriminates BAX from BAK regulation unresolved\", \"Channel function versus scaffolding contribution not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"VDAC2 KO with BAX retrotranslocation assays, peroxisomal fractionation and genetic rescue with BAK inhibitors\",\n      \"pmids\": [\"27620692\", \"28174205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of organelle targeting selectivity unknown\", \"Mechanism of retrotranslocation not reconstituted\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked VDAC2 to metabolic control by showing it binds PFKP to restrain glycolysis and suppress glioma stem-cell reprogramming.\",\n      \"evidence\": \"Co-IP, loss/gain-of-function with glycolysis and sphere-formation assays plus pharmacological rescue\",\n      \"pmids\": [\"30250190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether channel activity is required for PFKP regulation untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Unbiased genome-wide screening established VDAC2 as selectively essential for BAX, not BAK, apoptotic function, refining the dual-effector model.\",\n      \"evidence\": \"Genome-wide CRISPR screen, genetic deletion, blue native-PAGE and in vivo tumor assays\",\n      \"pmids\": [\"30478310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with BAK-sequestration role context-dependent\", \"Structural basis of differential effector handling open\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"31015432\", \"31591564\", \"31285435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ceramide pools engaging VDAC2 in vivo unmapped\", \"WEHI-9625 mechanism species-specific (mouse BAK)\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established VDAC2 abundance and activity as a node controlled by ubiquitination, O-GlcNAcylation and contact-site partners, tuning ferroptosis and apoptosis sensitivity.\",\n      \"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\",\n      \"pmids\": [\"31974380\", \"32641986\", \"36445063\", \"33067255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modified residues for ubiquitin/O-GlcNAc not all mapped\", \"Crosstalk between distinct PTMs untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"37416771\", \"30250190\", \"38149060\", \"36906852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs\", \"Direct link between N-terminal structural change and channel gating untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the precise BAK-VDAC2 interaction interface and characterized further degradation control (TRIM8) and structural features stabilizing VDAC2.\",\n      \"evidence\": \"Deep scanning mutagenesis with cysteine crosslinking and apoptosis assays; TRIM8 Co-IP/ubiquitination with ferroptosis rescue; high-resolution MS of intramolecular disulfide bridges\",\n      \"pmids\": [\"38696533\", \"38881325\", \"38832804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal/cryo-EM of the complex\", \"Functional roles of individual disulfides not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"40108474\", \"40069152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IFNγ tips the VDAC2-BAK balance mechanistically unresolved\", \"Selectivity of therapeutic window across tissues not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [9, 28, 29, 34]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6, 10, 13]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 5, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"VDAC2-BAK inactive complex\", \"VDAC2-BECN1-BCL2L1 complex\"],\n    \"partners\": [\"BAK1\", \"BAX\", \"STAR\", \"GSK3B\", \"PFKP\", \"BECN1\", \"STING1\", \"CKAP4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}