Affinage

VDAC3

Non-selective voltage-gated ion channel VDAC3 · UniProt Q9Y277

Length
283 aa
Mass
30.7 kDa
Annotated
2026-06-11
37 papers in source corpus 29 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VDAC3 is a mitochondrial outer membrane β-barrel channel that functions as a cysteine-based redox sensor and a non-redundant guardian of mitochondrial oxidative homeostasis and respiratory capacity [PMID:26407725, PMID:35180474, PMID:bio_10.1101_2025.02.20.639106]. Unlike VDAC1, native VDAC3 exhibits only weak voltage-dependent gating because an intramolecular disulfide bond tethers the N-terminal region to the pore base; reducing agents (DTT, GSNO) or cysteine mutation relieve this constraint and activate robust gating, establishing channel activity as redox-controlled (PMID:26407725). Native VDAC3 cysteines are extensively over-oxidized to sulfonic acid forms consistent with exposure to the oxidizing intermembrane space, and Cys2/Cys8 can form a disulfide bridge that controls pore stability and conductance (PMID:26760765, PMID:27989743). These cysteine residues are indispensable for VDAC3's protective role: cysteine-null mutants fail to counteract ROS-induced oxidative stress in human cells and fail to rescue oxidative-stress survival in yeast lacking endogenous VDACs and superoxide dismutases (PMID:35180474, PMID:40588209). VDAC3 loss is not compensated by VDAC1 or VDAC2, producing complex IV/electron transport chain deficits and a shift toward glutamine-dependent metabolism, defining a unique requirement in respiratory complex expression and metabolic adaptability [PMID:20875390, PMID:bio_10.1101_2025.02.20.639106]. The cysteine residues also tune isoform-specific interactions, attenuating VDAC3 binding to cytosolic regulators α-synuclein and tubulin relative to VDAC1 (PMID:31935282). Beyond mitochondria, VDAC3 localizes to the mother centriole, where it recruits Mps1 kinase to centrosomes to drive ciliary disassembly and suppress inappropriate ciliogenesis during cell cycle entry (PMID:22935710, PMID:23388454), and it is a structural constituent of sperm flagellum outer dense fibers (PMID:14739283). VDAC3 protein abundance is set by multiple E3 ubiquitin ligases acting through distinct linkages and stimuli—FBXW7 and SPOP target it for degradation in ferroptosis contexts, while Trim15 stabilizes it via K6-linked ubiquitination to suppress mitophagy (PMID:34869326, PMID:39549880, PMID:41617671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Established that VDAC3 exists as tissue-specific splice isoforms and that a methionine insertion near the N-terminus modulates its function, the first hint that the N-terminal region governs VDAC3 activity.

    Evidence Alternative splicing characterization and yeast complementation with subcellular localization in transfected mammalian cells

    PMID:9804816

    Open questions at the time
    • Did not define the channel/biophysical consequence of the methionine insertion
    • Functional difference between isoforms in mammalian mitochondria not resolved
  2. 2004 Medium

    Showed VDAC3 has an extramitochondrial structural role by localizing to sperm flagellum outer dense fibers, distinguishing it from VDAC1.

    Evidence Peptide sequencing, isoform-specific immunoblotting, immunofluorescence, and immuno-EM of purified bovine ODF

    PMID:14739283

    Open questions at the time
    • No mechanistic function for VDAC3 within ODF defined
    • Whether this reflects channel activity or purely structural incorporation is unknown
  3. 2010 Medium

    Defined VDAC3 as functionally distinct from VDAC1/VDAC2 — poor complementation of yeast respiration and ROS control — and mapped this deficit to the N-terminal 20 residues, while a knockout mouse revealed muscle-type-specific complex IV defects.

    Evidence Yeast complementation/respiration/ROS/lifespan assays, N-terminal domain-swap mutagenesis, and VDAC3-knockout mouse heart mitochondrial respirometry with EM

    PMID:20138821 PMID:20434446 PMID:20875390

    Open questions at the time
    • Molecular basis of reduced N-terminal activity not yet attributed to redox/cysteine state
    • Tissue specificity of the cardiac phenotype mechanistically unexplained
  4. 2012 Medium

    Revealed a non-mitochondrial role: VDAC3 at the mother centriole recruits Mps1 kinase to centrosomes to modulate centriole assembly.

    Evidence Co-immunoprecipitation, immunofluorescence localization, and Mps1 domain mapping

    PMID:22935710

    Open questions at the time
    • How VDAC3 is targeted to the centriole is unknown
    • Whether channel/redox function is required at the centriole not tested
  5. 2013 Medium

    Placed the VDAC3-Mps1 module in cell-cycle control of cilia, showing VDAC3 promotes ciliary disassembly and suppresses inappropriate ciliogenesis.

    Evidence siRNA depletion, GFP overexpression, and epistasis by independent Mps1 centrosome targeting with immunofluorescence

    PMID:23388454

    Open questions at the time
    • Upstream signals coupling cell cycle to VDAC3 centriolar function unknown
    • Link between mitochondrial and centriolar VDAC3 pools unresolved
  6. 2016 High

    Established the redox-sensor mechanism biophysically: native VDAC3 carries an N-terminal disulfide that suppresses gating, and reduction or cysteine mutation activates robust voltage-gating.

    Evidence Planar lipid bilayer reconstitution with DTT/GSNO treatment and cysteine mutants; native mass spectrometry identifying Cys2-Cys8 bridge and electrophysiology/complementation of cysteine mutants

    PMID:26407725 PMID:26760765

    Open questions at the time
    • In vivo redox state dynamics under physiological signaling not measured
    • Which cellular oxidoreductases set the disulfide state unknown
  7. 2016 Medium

    Mapped the native oxidative modification landscape, showing VDAC3 cysteines and methionines are over-oxidized consistent with intermembrane-space exposure, anchoring the redox-sensor model in physiological PTM chemistry.

    Evidence Protease mapping and UHPLC/high-resolution ESI-MS/MS of native rat liver mitochondrial VDAC3

    PMID:27989743

    Open questions at the time
    • Functional consequence of each over-oxidized residue not individually tested
    • Reversibility of sulfonic acid modifications in vivo unclear
  8. 2019 Medium

    Identified an aggregation-prone β7-β9 region buffered by an α1-β7-β9 interaction, linking N-terminal helix dynamics to VDAC3 folding stability.

    Evidence Systematic thiol replacement with far-UV CD and UV scattering spectroscopy

    PMID:30674561

    Open questions at the time
    • Whether aggregation occurs in cells is not shown
    • Relationship between folding intermediate and channel gating not established
  9. 2020 High

    Quantified isoform-specific channel behavior, showing VDAC3 forms conductive channels but engages α-synuclein and tubulin with markedly reduced kinetics governed by its cysteines.

    Evidence Planar lipid bilayer electrophysiology with cysteine scanning mutagenesis and kinetic analysis of α-synuclein/tubulin interactions

    PMID:31935282

    Open questions at the time
    • Physiological significance of attenuated regulator binding in cells untested
    • Which cysteines dominate regulator interaction not fully resolved
  10. 2022 High

    Demonstrated the cysteine residues are functionally indispensable for VDAC3's non-redundant antioxidant role in human cells, separating it from VDAC1.

    Evidence Isoform-specific siRNA knockdown plus wild-type vs cysteine-null mutant rescue in HAP1-ΔVDAC3 cells, high-resolution respirometry, and mitochondrial free radical measurement

    PMID:35180474

    Open questions at the time
    • Direct ROS-scavenging vs signaling mechanism not distinguished
    • Identity of physiological oxidant stresses VDAC3 buffers unknown
  11. 2022 Medium

    Connected VDAC3 modifications to disease-relevant and infection contexts: ALS-specific PTMs (including functionally validated Asn215 deamidation) and a direct enteroviral 2B interaction driving ROS-supported viral replication.

    Evidence nESI-MS/MS PTM mapping with Asn215 deamidation mutant electrophysiology; co-IP-proteomics of EV71 2B with siRNA knockdown and viral replication/ROS assays

    PMID:36016340 PMID:36555496

    Open questions at the time
    • Causality between ALS PTMs and disease not established
    • Structural basis of 2B-VDAC3 binding not determined
  12. 2021 Medium

    Initiated characterization of post-translational control of VDAC3 abundance, identifying FBXW7 as an E3 ligase coupling autophagy and the ubiquitin-proteasome system to VDAC3-dependent ferroptosis sensitivity.

    Evidence Co-IP, lentiviral knockdown/overexpression, UbiBrowser prediction with experimental confirmation, and xenograft model

    PMID:34869326

    Open questions at the time
    • Degron on VDAC3 recognized by FBXW7 not mapped
    • Whether redox state influences ligase recognition unknown
  13. 2023 Medium

    Showed VDAC3 is a covalent small-molecule target, with dankastatin B modifying Cys65 to exert anticancer activity, validating VDAC3 cysteines as druggable.

    Evidence Activity-based protein profiling chemoproteomics, covalent interaction demonstration, and VDAC3 knockdown sensitivity assay

    PMID:36798342 PMID:36964942

    Open questions at the time
    • Functional consequence of Cys65 modification on channel activity not measured
    • Downstream pathway from VDAC3 engagement to cytotoxicity unclear
  14. 2024 Medium

    Expanded the regulatory network with SPOP-mediated degradation under m6A control and an ACSL4-bridged ZIP7-VDAC3 axis routing ER-to-mitochondria iron transfer, linking VDAC3 to ferroptotic iron handling.

    Evidence Co-IP, Me-RIP/RIP/luciferase assays in cardiomyocytes (SPOP/ALKBH5/IGF2BP2); co-IP and organelle iron measurement with VDAC3/ZIP7 knockdown in vivo (ACSL4-ZIP7-VDAC3)

    PMID:39549880 PMID:39579909

    Open questions at the time
    • Whether VDAC3 channels iron directly or scaffolds the transfer complex unresolved
    • Integration of multiple competing ligases on the same VDAC3 pool unclear
  15. 2025 Medium

    Consolidated VDAC3's non-redundant respiratory role and added new layers of regulation: ETC complex downregulation and glutamine dependence upon knockout, K6-linked stabilization by Trim15 suppressing mitophagy, m6A/HECTD1 control of abundance, lipid (cardiolipin) modulation of gating, and inter-isoform disulfide oligomerization.

    Evidence CRISPR KO with proteomics/metabolic phenotyping (HeLa, preprint); co-IP and functional assays for Trim15 K6-ubiquitination; Me-RIP/HECTD1 co-IP with in vivo models; single-channel electrophysiology with MD simulation for lipid effects; MS/MS disulfide mapping of homo-/hetero-oligomers; yeast complementation confirming cysteine-dependent protection

    PMID:39379688 PMID:40588209 PMID:40875006 PMID:41575209 PMID:41617671 PMID:42158826

    Open questions at the time
    • KO metabolic phenotype is from a preprint not yet peer-reviewed
    • Physiological role of VDAC3-VDAC1/VDAC2 disulfide oligomers untested
    • How distinct ligases are selected by stimulus not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VDAC3's redox-sensing cysteine state is set and dynamically tuned in vivo, and how this couples its channel gating, centriolar Mps1 recruitment, iron handling, and ligase-controlled stability into a unified regulatory logic, remains unresolved.
  • No in vivo measurement of VDAC3 disulfide state under defined redox signaling
  • No structural model linking N-terminal disulfide to gating and partner binding
  • Mechanistic connection between mitochondrial and centriolar VDAC3 functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140299 molecular sensor activity 4 GO:0005215 transporter activity 3 GO:0005198 structural molecule activity 1
Localization
GO:0005739 mitochondrion 3 GO:0005815 microtubule organizing center 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 2
Partners
ACSL4FBXW7HECTD1MPS1SNCASPOPTRIM15ZIP7

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 VDAC2 and VDAC3 are abundant proteins in bovine sperm outer dense fibers (ODF), a cytoskeletal component of the flagellum, localizing to this non-membranous structure as demonstrated by peptide sequencing, immunoblotting with isoform-specific antibodies, immunofluorescence microscopy, and transmission electron immunomicroscopy. Only VDAC2 and VDAC3 (not VDAC1) were found in purified ODF preparations, suggesting an alternative structural organization and function outside mitochondria. Peptide sequencing, isoform-specific antibody immunoblotting, immunofluorescence microscopy, transmission electron immunomicroscopy The Journal of biological chemistry Medium 14739283
1998 VDAC3 has an alternatively spliced isoform generated by tissue-specific inclusion of a 3-base exon encoding methionine 39 amino acids downstream of the N-terminus, expressed in brain, heart, and skeletal muscle. Both isoforms localize to mitochondria in transfected mammalian cells. Complementation of YVDAC-deficient yeast indicates this methionine residue is an important modulator of VDAC3 function. Alternative splicing characterization, yeast complementation assay, subcellular localization by transfection/imaging The Journal of biological chemistry Medium 9804816
2010 VDAC3 has limited ability to complement the lack of endogenous porin in yeast mitochondrial respiration and has no influence on ROS production control, unlike VDAC1 and VDAC2. Over-expression of VDAC3 causes dramatic sensitivity to oxidative stress and shorter lifespan in yeast under respiratory conditions. Yeast complementation assay, respiratory assay, ROS assay, lifespan analysis Biochimica et biophysica acta Medium 20138821
2010 Swapping the N-terminal 20 amino acids of VDAC3 with those of VDAC1 restores full channel activity: the chimera complements yeast porin-deficient strains for mitochondrial respiration, modulates ROS, and increases lifespan. This demonstrates that the N-terminal region of VDAC3 is the primary determinant of its reduced activity compared to VDAC1. N-terminal domain swap mutagenesis, yeast complementation assay, respiratory assay, ROS assay, lifespan analysis FEBS letters Medium 20434446
2010 In VDAC3-deficient mouse hearts (but not gastrocnemius), there is decreased apparent affinity of in situ mitochondria for ADP and a specific defect restricted to respiratory complex IV activity, accompanied by structural mitochondrial aberrations. This demonstrates muscle-type specificity for VDAC3 function distinct from VDAC1. VDAC3 knockout mouse model, in situ mitochondrial respiration assay, respiratory enzyme activity measurement, electron microscopy Biochimica et biophysica acta Medium 20875390
2012 VDAC3 localizes to the mother centriole and recruits the Mps1 kinase to centrosomes by binding to a centrosome localization domain within Mps1, thereby modulating centriole assembly. This was established by identification of a VDAC3-Mps1 interaction and showing VDAC3 presence at the mother centriole. Co-immunoprecipitation, immunofluorescence localization, domain mapping Cell cycle (Georgetown, Tex.) Medium 22935710
2013 VDAC3 depletion causes inappropriate ciliogenesis in cycling cells, while GFP-VDAC3 expression suppresses ciliogenesis in quiescent cells. The VDAC3-Mps1 module at the centrosome promotes ciliary disassembly during cell cycle entry; inappropriate ciliogenesis caused by VDAC3 depletion can be bypassed by targeting Mps1 to centrosomes independently of VDAC3. siRNA depletion, GFP overexpression, epistasis by independent Mps1 centrosome targeting, immunofluorescence Cell cycle (Georgetown, Tex.) Medium 23388454
2016 Cysteine residues 2 and 8 of VDAC3 can form a disulfide bridge in native rat liver mitochondrial VDAC3, as shown by mass spectrometry. Single and combined site-directed mutagenesis of cysteines 2, 8, and 122 demonstrated that these residues influence protein mobility, pore stability (by electrophysiology), and the ability to complement porin-less yeast. A positive correlation was found between pore conductance of cysteine mutants and their complementation ability. VDAC3 cysteines act as a redox sensor in the intermembrane space. Mass spectrometry (native VDAC3), site-directed mutagenesis of cysteines, electrophysiology (planar lipid bilayer), SDS-PAGE mobility analysis, yeast complementation assay Oncotarget High 26760765
2015 VDAC3 has weak voltage-dependent gating activity in its native form due to an intramolecular disulfide bond linking the N-terminal region to the bottom of the pore. Treatment with DTT or GSNO (redox agents that suppress disulfide bond formation) activates robust gating activity. Cysteine mutants of VDAC3 also exhibit typical voltage-gating, confirming that the disulfide bond suppresses gating and that VDAC3 channel gating is redox-controlled. Reconstitution in planar lipid bilayers, site-directed cysteine mutagenesis, treatment with DTT and GSNO Biochimica et biophysica acta High 26407725
2016 High-resolution mass spectrometry of rat liver mitochondrial VDAC3 revealed that in physiological conditions, cysteine residues 36, 65, and 165 are extensively oxidized to sulfonic acid, Cys229 is exclusively in sulfonic acid form, methionines are oxidized to methionine sulfoxide, and Cys2/Cys8 are detected in carboxyamidomethylated form. This over-oxidation pattern is consistent with exposure of these residues to the strongly oxidizing intermembrane space. SDS-PAGE, tryptic/chymotryptic proteolysis, UHPLC/High Resolution ESI-MS/MS Biochimica et biophysica acta. Biomembranes Medium 27989743
2020 VDAC3 forms stable, highly conductive voltage-gated channels that facilitate metabolite exchange but interact with cytosolic regulators α-synuclein and tubulin with 10- to 100-fold reduced on-rates compared to VDAC1, and with altered α-synuclein blocking times. Cysteine scanning mutagenesis demonstrated that VDAC3's cysteine residues regulate its interaction with α-synuclein, establishing isoform-specific functional properties. Planar lipid bilayer electrophysiology, cysteine scanning mutagenesis, protein-channel interaction kinetics with α-synuclein and tubulin The Journal of general physiology High 31935282
2014 VDAC3 interacts with a broad set of cytosolic, mitochondrial, cytoskeletal, and ER proteins in HeLa cells, including tubulins, cytoskeletal proteins, stress sensors, chaperones, proteasome components, and protein disulfide isomerase. These interactions were identified by tandem-affinity purification/MS and validated by co-immunoprecipitation. Live cell imaging confirmed VDAC3 localizes to mitochondria. Stable cell line with dual-tagged VDAC3, tandem-affinity purification, 2D-gel electrophoresis, mass spectrometry, co-immunoprecipitation, live cell imaging Molecular bioSystems Medium 24865465
2021 FBXW7 was identified as the specific E3 ubiquitin ligase for VDAC3, mediating its ubiquitination and proteasomal degradation. Autophagy regulates VDAC3 protein levels post-transcriptionally via this ubiquitin-proteasome system. FBXW7 knockdown attenuated VDAC3 ubiquitination and degradation, increasing sensitivity of ALL cells to erastin-induced ferroptosis. Co-immunoprecipitation, lentiviral knockdown/overexpression, UbiBrowser prediction followed by experimental confirmation, in vivo xenograft model Frontiers in cell and developmental biology Medium 34869326
2022 FBXW7 regulates VDAC3 protein expression through ubiquitination, and this is controlled upstream by the lncRNA BDNF-AS/WDR5 axis which regulates FBXW7 transcription. This axis modulates ferroptosis in gastric cancer cells. ChIRP, RIP, ChIP, co-immunoprecipitation, in vivo validation International journal of biological sciences Medium 35280682
2022 VDAC3 depletion reduces mitochondrial ROS generation induced by EV71 infection. Co-immunoprecipitation-proteomic analysis revealed that enteroviral 2B protein directly interacts with VDAC3. VDAC3 knockdown inhibited enteroviral replication and reduced 2B-induced mitochondrial ROS. VDAC3 knockdown enhanced antioxidant hypotaurine/taurine metabolism in infected cells, indicating VDAC3 is necessary for 2B-mediated ROS enhancement that supports viral replication. Co-immunoprecipitation-proteomics, siRNA knockdown, single-round viral replication assay, mitochondrial ROS measurement Viruses Medium 36016340
2022 Depletion of VDAC3 (but not VDAC1) significantly exacerbates cytotoxicity of redox cyclers (menadione, paraquat) and complex I inhibitors (rotenone), promoting accumulation of mitochondrial free radicals. High-resolution respirometry of HAP1-ΔVDAC3 cells expressing wild-type or cysteine-null mutant VDAC3 confirmed that VDAC3 cysteine residues are indispensable for its ability to counteract ROS-induced oxidative stress. siRNA knockdown of VDAC3 vs VDAC1, transient transfection of wild-type vs cysteine-null mutant, high-resolution respirometry, mitochondrial free radical measurement Redox biology High 35180474
2022 VDAC3 post-translational modifications specific to ALS-related oxidative stress include over-oxidation, deamidation, and succination detected in NSC34-SOD1G93A cells but not in non-ALS lines. Deamidation of Asn215 alone alters single-channel behavior in artificial membranes, demonstrating a direct functional effect of this modification on channel activity. nUHPLC/High-Resolution nESI-MS/MS, single-channel electrophysiology in artificial membranes with Asn215 deamidation mutant International journal of molecular sciences Medium 36555496
2023 Dankastatin B covalently targets cysteine C65 of VDAC3 as its primary cellular target in breast cancer cells, identified by activity-based protein profiling chemoproteomic approaches. Direct covalent interaction was demonstrated. VDAC3 knockdown conferred hypersensitivity to dankastatin B, indicating VDAC3 is at least partially responsible for its anticancer activity. Activity-based protein profiling (chemoproteomic), direct covalent interaction demonstration, VDAC3 knockdown sensitivity assay Chembiochem : a European journal of chemical biology Medium 36798342 36964942
2019 The region comprising strands β7-β9 of hVDAC3 is highly aggregation-prone. An α1-β7-β9 interaction involving the N-terminal α1 helix lowers protein aggregation, and perturbation of this interaction promotes VDAC3 aggregation via a partially unfolded intermediate. This was mapped by systematic thiol replacement combined with CD spectropolarimetry and UV scattering spectroscopy. Systematic thiol replacement (cysteine-scanning), far-UV circular dichroism, UV scattering spectroscopy The Journal of general physiology Medium 30674561
2024 SPOP E3 ubiquitin ligase facilitates ubiquitination and degradation of VDAC3. ALKBH5 m6A demethylase reduces SPOP mRNA stability (via m6A at its 3'UTR), thereby inhibiting SPOP-induced VDAC3 degradation and promoting ferroptosis, while IGF2BP2 enhances SPOP mRNA stability to suppress ferroptosis via VDAC3 degradation. Co-immunoprecipitation, western blot, Me-RIP (m6A assay), RIP, luciferase reporter assay, overexpression/knockdown in cardiomyocytes Free radical biology & medicine Medium 39549880
2025 ALKBH5 inhibits VDAC3 m6A modification (reducing its mRNA stability), while YTHDF1 is the m6A reader that enhances VDAC3 mRNA stability. ALKBH5 knockdown decreased etoposide-induced senescence and promoted osteogenic differentiation in BMSCs, effects reversed by VDAC3 knockdown, placing VDAC3 downstream of ALKBH5-mediated m6A regulation. Me-RIP assay, RNA immunoprecipitation (RIP), luciferase reporter assay, ALKBH5/YTHDF1 overexpression/knockdown, qPCR Scientific reports Medium 39379688
2025 HECTD1 is the E3 ubiquitin ligase that interacts with and ubiquitinates VDAC3 under hypothermic conditions. Therapeutic hypothermia increased HECTD1-VDAC3 interaction and VDAC3 ubiquitination; HECTD1 knockdown reversed hypothermia-induced neuroprotection and anti-apoptotic effects in a rat cardiac arrest/CPR model. Co-immunoprecipitation, double immunofluorescence, western blot, adeno-associated viral siRNA knockdown, in vivo rat model International journal of medical sciences Medium 42158826
2025 Cardiolipin uniquely disrupts hVDAC3 gating by preferentially retaining the channel in an open-like conductive state, while physiological lipids (anionic headgroups, negative protein-bilayer mismatch, increased membrane viscosity) favor optimal channel stability and function. Single-channel electrophysiology combined with all-atom molecular dynamics simulations showed that lipid composition selectively modulates hVDAC3 structure and N-terminal helix dynamics without altering the global β-barrel fold. Single-channel electrophysiology (planar lipid bilayer), all-atom molecular dynamics simulations, systematic variation of lipid composition Protein science : a publication of the Protein Society Medium 41575209
2025 High-resolution mass spectrometry identified three intramolecular disulfide bonds in rat VDAC3 and seven intermolecular disulfide bonds between VDAC3 and VDAC1 or VDAC2. This demonstrates that VDAC3 participates in homo- and hetero-oligomerization of VDAC isoforms via disulfide bridges. UHPLC/High Resolution ESI-MS/MS, enzymatic digestion, MS/MS-based disulfide mapping Analytical and bioanalytical chemistry Medium 40875006
2026 Trim15 E3 ubiquitin ligase stabilizes VDAC3 via K6-linked ubiquitination (rather than targeting it for degradation). VDAC3 stabilization by Trim15 suppresses autophagy and mitophagy while elevating ROS; VDAC3 knockdown enhances autophagy/mitophagy and reduces ROS, promoting cancer cell survival. Co-immunoprecipitation, immunoblotting, lentiviral knockdown/overexpression, xenograft model, autophagy/mitophagy assays, ROS measurement Cell death discovery Medium 41617671
2025 In HeLa cells with VDAC3 knockout, key members of the electron transport chain are dramatically downregulated and mitochondria shift to a glutamine-dependent metabolic state. This phenotype is not compensated by VDAC1 or VDAC2, revealing a non-redundant role of VDAC3 in supporting mitochondrial respiratory complex expression and metabolic adaptability. CRISPR/functional KO in HeLa cells, comparative proteomics, metabolic activity assays (respirometry, glycolysis), transcriptomics bioRxivpreprint Medium bio_10.1101_2025.02.20.639106
2025 hVDAC3 expressing yeast (lacking endogenous VDACs and superoxide dismutases) showed stable growth under oxidative stress, maintained mitochondrial membrane potential and morphology, reduced superoxide levels, and achieved efficient ATP synthesis with minimal proton leak. A cysteine-depleted variant (hVDAC3ΔCys) showed impaired growth under stress, confirming that cysteine residues are essential for the protective function of hVDAC3 against oxidative stress. Yeast complementation in POR1/POR2/SOD1/SOD2-deficient strain, mitochondrial membrane potential assay, morphology imaging, superoxide measurement, bioenergetic profiling Biochimica et biophysica acta. Bioenergetics Medium 40588209
2024 ACSL4 interacts with both ZIP7 (ER iron efflux channel) and VDAC3 (mitochondrial outer membrane) in mouse liver and human hepatocytes under PFOS exposure, facilitating ER-to-mitochondria iron transfer. Knockdown of VDAC3 reversed PFOS-induced mitochondrial iron overload and aggravated ER iron accumulation. Inhibition of ACSL4 reduced the ZIP7-VDAC3 interaction and mitigated mitochondrial iron overload. Co-immunoprecipitation (ACSL4-ZIP7, ACSL4-VDAC3), siRNA knockdown of VDAC3 and ZIP7, iron measurement in organellar fractions, in vivo mouse model The Science of the total environment Medium 39579909

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Characterization of human VDAC isoforms: a peculiar function for VDAC3? Biochimica et biophysica acta 137 20138821
2004 Voltage-dependent anion-selective channels VDAC2 and VDAC3 are abundant proteins in bovine outer dense fibers, a cytoskeletal component of the sperm flagellum. The Journal of biological chemistry 96 14739283
2022 The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination. International journal of biological sciences 94 35280682
2016 VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications. Oncotarget 84 26760765
2015 VDAC3 gating is activated by suppression of disulfide-bond formation between the N-terminal region and the bottom of the pore. Biochimica et biophysica acta 62 26407725
2022 Voltage Dependent Anion Channel 3 (VDAC3) protects mitochondria from oxidative stress. Redox biology 60 35180474
2016 VDAC3 As a Potential Marker of Mitochondrial Status Is Involved in Cancer and Pathology. Frontiers in oncology 60 28066720
2004 All three isoforms of the voltage-dependent anion channel (VDAC1, VDAC2, and VDAC3) are present in mitochondria from bovine, rabbit, and rat brain. Archives of biochemistry and biophysics 58 14759607
2010 Swapping of the N-terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti-aging features to the cell. FEBS letters 55 20434446
1998 A novel isoform of the mitochondrial outer membrane protein VDAC3 via alternative splicing of a 3-base exon. Functional characteristics and subcellular localization. The Journal of biological chemistry 52 9804816
2020 A lower affinity to cytosolic proteins reveals VDAC3 isoform-specific role in mitochondrial biology. The Journal of general physiology 48 31935282
2013 VDAC3 and Mps1 negatively regulate ciliogenesis. Cell cycle (Georgetown, Tex.) 45 23388454
2021 Autophagy Regulates VDAC3 Ubiquitination by FBXW7 to Promote Erastin-Induced Ferroptosis in Acute Lymphoblastic Leukemia. Frontiers in cell and developmental biology 44 34869326
2010 VDAC3 has differing mitochondrial functions in two types of striated muscles. Biochimica et biophysica acta 37 20875390
2014 Differential targeting of VDAC3 mRNA isoforms influences mitochondria morphology. Proceedings of the National Academy of Sciences of the United States of America 35 24889622
2018 miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3. Journal of experimental & clinical cancer research : CR 32 29378599
2016 High resolution mass spectrometry characterization of the oxidation pattern of methionine and cysteine residues in rat liver mitochondria voltage-dependent anion selective channel 3 (VDAC3). Biochimica et biophysica acta. Biomembranes 31 27989743
2012 VDAC3 regulates centriole assembly by targeting Mps1 to centrosomes. Cell cycle (Georgetown, Tex.) 25 22935710
2014 Live cell interactome of the human voltage dependent anion channel 3 (VDAC3) revealed in HeLa cells by affinity purification tag technique. Molecular bioSystems 24 24865465
2022 Enteroviral 2B Interacts with VDAC3 to Regulate Reactive Oxygen Species Generation That Is Essential to Viral Replication. Viruses 23 36016340
2019 Helix-strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3. The Journal of general physiology 16 30674561
2017 Association of the VDAC3 gene polymorphism with sperm count in Han-Chinese population with idiopathic male infertility. Oncotarget 16 28431403
2024 N6-methyladenosine modification of SPOP relieves ferroptosis and diabetic cardiomyopathy by enhancing ubiquitination of VDAC3. Free radical biology & medicine 14 39549880
2024 ALKBH5 regulates etoposide-induced cellular senescence and osteogenic differentiation in osteoporosis through mediating the m6A modification of VDAC3. Scientific reports 12 39379688
2022 Specific Post-Translational Modifications of VDAC3 in ALS-SOD1 Model Cells Identified by High-Resolution Mass Spectrometry. International journal of molecular sciences 10 36555496
2024 ACSL4-mediated ZIP7-VDAC3 interaction regulates endoplasmic reticulum-mitochondria iron transfer in hepatocytes under PFOS exposure. The Science of the total environment 6 39579909
2023 Chemoproteomic Profiling Reveals that Anticancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3. Chembiochem : a European journal of chemical biology 6 36964942
2025 Fto-dependent Vdac3 m6A Modification Regulates Neuronal Ferroptosis Induced by the Post-ICH Mass Effect and Transferrin. Neuroscience bulletin 4 39951182
2025 Human VDAC3 as a sensor of the intracellular redox state: contribution to cytoprotection mechanisms in oxidative stress. Biochimica et biophysica acta. Bioenergetics 4 40588209
2025 The VDAC3/DHODH Axis Ameliorates Sepsis-induced Myocardial Injury by Regulating Ferroptosis. Frontiers in bioscience (Landmark edition) 3 40613295
2018 LSCC SNP variant regulates SOX2 modulation of VDAC3. Oncotarget 3 29854282
2023 Chemoproteomic Profiling Reveals that Anti-Cancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3. bioRxiv : the preprint server for biology 2 36798342
2026 Protein-lipid interplay governs ion channel gating and bioenergetics in human mitochondrial VDAC3. Protein science : a publication of the Protein Society 1 41575209
2026 Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma. Cell death discovery 0 41617671
2026 PRELID1 and VDAC3 Coordinate a Senescence-Like State in Germinal Center B Cells to Promote IL-7-Driven Antitumor Immunity in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41706757
2026 Therapeutic Hypothermia Ameliorates Apoptosis and Cerebral Injury by Upregulating HECTD1-mediated Ubiquitination and VDAC3 Degradation in a Rat CPR Model. International journal of medical sciences 0 42158826
2025 Structural characterization of intra- and intermolecular disulfide bonds in voltage-dependent anion channel 3 (VDAC3) protein from Rattus norvegicus by high-resolution mass spectrometry. Analytical and bioanalytical chemistry 0 40875006

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