VDAC1

Summary

VDAC1 (voltage dependent anion channel 1, HGNC:12669) is a protein-coding gene on chromosome 5q31.1, encoding Non-selective voltage-gated ion channel VDAC1 (P21796). Non-selective voltage-gated ion channel that mediates the transport of anions and cations through the mitochondrion outer membrane and plasma membrane. It is a selective cancer dependency (DepMap: 72.1% of cell lines).

This gene encodes a voltage-dependent anion channel protein that is a major component of the outer mitochondrial membrane. The encoded protein facilitates the exchange of metabolites and ions across the outer mitochondrial membrane and may regulate mitochondrial functions. This protein also forms channels in the plasma membrane and may be involved in transmembrane electron transport. Alternate splicing results in multiple transcript variants. Multiple pseudogenes of this gene are found on chromosomes 1, 2 3, 6, 9, 12, X and Y.

Source: NCBI Gene 7416 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 38 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 72.1% of screened cell lines
• MANE Select transcript: NM_003374

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12669
Approved symbol	VDAC1
Name	voltage dependent anion channel 1
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC111064, PORIN
Ensembl gene	ENSG00000213585
Ensembl biotype	protein_coding
OMIM	604492
Entrez	7416

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 50 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265333, ENST00000395044, ENST00000395047, ENST00000425992, ENST00000466080, ENST00000489906, ENST00000492324, ENST00000876053, ENST00000876054, ENST00000876055, ENST00000876056, ENST00000876057, ENST00000876058, ENST00000876059, ENST00000876060, ENST00000876061, ENST00000876062, ENST00000876063, ENST00000876064, ENST00000876065, ENST00000876066, ENST00000876067, ENST00000876068, ENST00000876069, ENST00000876070, ENST00000876071, ENST00000876072, ENST00000876073, ENST00000876074, ENST00000876075, ENST00000876076, ENST00000876077, ENST00000935308, ENST00000935309, ENST00000935310, ENST00000935311, ENST00000935312, ENST00000935313, ENST00000935314, ENST00000961136, ENST00000961137, ENST00000961138, ENST00000961139, ENST00000961140, ENST00000961141, ENST00000961142, ENST00000961143, ENST00000961144, ENST00000961145, ENST00000961146, ENST00000961147, ENST00000961148, ENST00000961149

RefSeq mRNA: 20 — MANE Select: NM_003374 NM_001401008, NM_001401009, NM_001401010, NM_001401011, NM_001401016, NM_001401017, NM_001401018, NM_001401020, NM_001401021, NM_001401022, NM_001401023, NM_001401024, NM_001401025, NM_001401026, NM_001401027, NM_001401028, NM_001401029, NM_001401031, NM_001401032, NM_003374

CCDS: CCDS4168

Canonical transcript exons

ENST00000265333 — 9 exons

Exon	Start	End
ENSE00001404799	134004895	134004975
ENSE00003487627	133991002	133991154
ENSE00003551770	133992306	133992355
ENSE00003570560	133973791	133973848
ENSE00003580434	133990855	133990907
ENSE00003638547	133992946	133993018
ENSE00003647304	133975871	133976021
ENSE00003784323	133980729	133980956
ENSE00003848965	133971871	133972862

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 176.2842 / max 975.0310, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63418	165.3740	1826
63419	8.6294	1672
63420	1.3483	928
63421	0.5417	194
63416	0.2645	124
63417	0.1263	37

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	99.51	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.41	gold quality
gastrocnemius	UBERON:0001388	99.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.34	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.32	gold quality
jejunal mucosa	UBERON:0000399	99.30	gold quality
muscle of leg	UBERON:0001383	99.29	gold quality
vastus lateralis	UBERON:0001379	99.27	gold quality
muscle organ	UBERON:0001630	99.23	gold quality
skeletal muscle organ	UBERON:0014892	99.23	gold quality
heart right ventricle	UBERON:0002080	99.17	gold quality
skeletal muscle tissue	UBERON:0001134	99.12	gold quality
heart left ventricle	UBERON:0002084	99.08	gold quality
cardiac ventricle	UBERON:0002082	99.06	gold quality
gluteal muscle	UBERON:0002000	98.99	gold quality
quadriceps femoris	UBERON:0001377	98.97	gold quality
triceps brachii	UBERON:0001509	98.97	gold quality
mucosa of transverse colon	UBERON:0004991	98.97	gold quality
muscle tissue	UBERON:0002385	98.92	gold quality
apex of heart	UBERON:0002098	98.91	gold quality
right atrium auricular region	UBERON:0006631	98.89	gold quality
deltoid	UBERON:0001476	98.88	gold quality
diaphragm	UBERON:0001103	98.82	gold quality
cardiac atrium	UBERON:0002081	98.82	gold quality
myocardium	UBERON:0002349	98.78	gold quality
heart	UBERON:0000948	98.72	gold quality
left ventricle myocardium	UBERON:0006566	98.71	gold quality
colonic mucosa	UBERON:0000317	98.70	gold quality
rectum	UBERON:0001052	98.70	gold quality
islet of Langerhans	UBERON:0000006	98.69	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	56.36
E-MTAB-7316	yes	36.06
E-MTAB-10042	yes	16.93
E-GEOD-137537	yes	13.49
E-MTAB-7606	no	524.28
E-MTAB-10596	no	370.07
E-HCAD-6	no	40.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARG

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 72.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• interacts with the dynein light chain Tctex1 and the heat-shock protein PBP74; results of this study represent additional evidence of membrane-associated trafficking of the voltage-dependent anion-selective channel 1 (PMID:12009301)
• Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic protein Bim (PMID:12118373)
• Presence of a plasma membrane VDAC was demonstrated. Colocalisation of VDAC with caveolin-1. (PMID:12698369)
• is a receptor for plasminogen kringle 5 on endothelial cells (PMID:12736244)
• Identification of the protein-protein contact site and interaction mode of VDAC1 with Bcl-2 family proteins. (PMID:12767928)
• a major function of VDAC1 in the plasma membrane is that of a NADH(-ferricyanide) reductase that may be involved in the maintenance of cellular redox homeostasis (PMID:14573604)
• VDAC homodimerization could potentially determine its gating capacity to cyto c, and Bcl-2 blockage of VDAC homodimerization represents a novel mechanism for its inhibition of apoptosis. (PMID:14647451)
• a model on how electron transport may occur in VDAC1. (PMID:15630200)
• evidences of VDAC-COX interaction in vitro proved to be functional as evidenced by the effect of the human and yeast isoforms of VDAC on the oxidation of cytochrome c by the pure holoenzyme and by the effect of the COX epitope on VDAC permeability (PMID:16185087)
• VDAC1 regulates apoptosis independent of the apoptosis-inducing pathway. (PMID:16585511)
• Bcl-xL can bind to one or two VDAC1 molecules forming heterodimers and heterotrimers. (PMID:17209561)
• gelsolin G5 domain inhibits HIV-Vpr-induced T-cell apoptosis by blocking the interaction between Vpr and VDAC (PMID:17254575)
• hVDAC1 formed different structures in detergent micelles and phospholipid bilayers. (PMID:17336328)
• Our analysis strongly suggests a 16-stranded, antiparallel beta-barrel with one large and seven short loops and turns. Initial crystallization trials of the protein yielded crystals diffracting to 8 Angstrom resolution. (PMID:17828567)
• phosphorylated StAR interacts with voltage-dependent anion channel 1 (VDAC1) on the OMM, which then facilitates processing of the 37-kDa phospho-StAR to the 32-kDa intermediate. (PMID:18250166)
• interference with the binding of Hexokinase-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents (PMID:18308720)
• VDAC1 may act as a facultative regulator/effector of MMP, depending on the initial cytotoxic event. (PMID:18362892)
• two serine residues of VDAC1, Ser-12 and Ser-103, can modulate VDAC1 protein level and thus the sensitivity to apoptosis stimuli (PMID:18381814)
• Human voltage-dependent anion selective channel 1 is a target antigen for anti-glomerular endothelial cell antibody in mixed connective tissue disease. (PMID:18568384)
• High-resolution structure analysis of human VDAC1 crystal lattice reveals that it belongs to trigonal space group P321, with unit-cell parameters a = 78.9, c = 165.7 A and one monomer in the asymmetric unit. (PMID:18607100)
• Approaching the structure of human VDAC1, a key molecule in mitochondrial cross-talk. (PMID:18690523)
• study presents NMR solution structure of recombinant VDAC-1 reconstituted in detergent micelles (PMID:18755977)
• the 3D structure of human VDAC1, which was solved conjointly by NMR spectroscopy and x-ray crystallography (PMID:18832158)
• results point to HK-I and HK-II as promoting tumor cell survival through binding to VDAC1, thereby inhibiting cytochrome c release and apoptotic cell death. (PMID:19049977)
• Displacing hexokinase from its binding site on VDAC1 may be exploited as an approach to cancer therapy. (PMID:19094960)
• Data demonstrate in caveolae of human cortex and hippocampus the presence of pl-VDAC and ERalpha, in a complex with scaffolding caveolin-1 which likely provides ERalpha stability at the plasma membrane. (PMID:19595769)
• Our data thus support a model of the PTP complex involving VDAC1 at the MOM, and indicate that VDAC1-dependent MPT is an upstream mechanism playing a causal role in oxidative stress-induced apoptosis. (PMID:19668262)
• The dynamics of the molecular interactions between the C-terminal region of PB1-F2 protein and VDAC1 and ANT3 were expounded by employing an in silico approach. (PMID:19669810)
• a VDAC1-containing mitochondrial system is involved in PQ poisoning (PMID:19717555)
• Data identified VDAC1 (voltage-dependent anion channel 1) as a target for Parkin-mediated Lys 27 poly-ubiquitylation and mitophagy. (PMID:20098416)
• The length of the tag at the C-terminus is critical for the assembly of VDAC1, as well as the amino acid residues at positions 130, 222, 225 and 251 of the protein. (PMID:20117113)
• H. pylori VacA p58 (vacuolating cytotoxin A p58 domain) induced apoptosis in gastric epithelial carcinoma cells and was associated with the up-regulation of Bax/VDAC1 (voltage-dependent anion channel 1) and the downregulation of Bcl-2 (PMID:20132430)
• Data suggest that the two cysteine residues are not required for apoptosis or VDAC1 oligomerization. (PMID:20192921)
• these data provide a mechanism to explain how Nek1 regulates cell death by affecting the opening and closing of VDAC1. (PMID:20230784)
• FimA strengthens the VDAC1-hexokinase interaction and prevents dissociation of hexokinase from VDAC1 triggered by apoptotic stimuli. (PMID:20347420)
• The results of this study demonstrate, for the first time, the anticancer therapeutic potential of VDAC1 downregulation by means of shRNA. (PMID:20404552)
• The substitution of the VDAC3 N-terminus with the VDAC1 N-terminus caused the chimaera to become more active than VDAC1. (PMID:20434446)
• describe the crystallization of voltage-dependent anion channel-1 produced by a bacterial cell-free expression system (PMID:20435015)
• VDAC1 expression was not altered cervical neoplasms. (PMID:20846459)
• Mitochondria are aggregated by p62, following its recruitment by Parkin in a VDAC1-independent manner. (PMID:20890124)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	vdac1	ENSDARG00000045132
mus_musculus	Vdac1	ENSMUSG00000020402
rattus_norvegicus	Vdac1	ENSRNOG00000006375
drosophila_melanogaster	porin	FBGN0004363
drosophila_melanogaster	Porin2	FBGN0069354
drosophila_melanogaster	CG17140	FBGN0260453
drosophila_melanogaster	CG17139	FBGN0260454

Paralogs (2): VDAC3 (ENSG00000078668), VDAC2 (ENSG00000165637)

Protein

Protein identifiers

Non-selective voltage-gated ion channel VDAC1 — P21796 (reviewed: P21796)

Alternative names: Outer mitochondrial membrane protein porin 1, Plasmalemmal porin, Porin 31HL, Porin 31HM, Voltage-dependent anion-selective channel protein 1

All UniProt accessions (3): A0A1L1UHR1, C9JI87, P21796

UniProt curated annotations — full annotation on UniProt →

Function. Non-selective voltage-gated ion channel that mediates the transport of anions and cations through the mitochondrion outer membrane and plasma membrane. The channel at the outer mitochondrial membrane allows diffusion of small hydrophilic molecules; in the plasma membrane it is involved in cell volume regulation and apoptosis. It adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The open state has a weak anion selectivity whereas the closed state is cation-selective. Binds various signaling molecules, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterols cholesterol and oxysterol. In depolarized mitochondria, acts downstream of PRKN and PINK1 to promote mitophagy or prevent apoptosis; polyubiquitination by PRKN promotes mitophagy, while monoubiquitination by PRKN decreases mitochondrial calcium influx which ultimately inhibits apoptosis. May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis. May mediate ATP export from cells. Part of a complex composed of HSPA9, ITPR1 and VDAC1 that regulates mitochondrial calcium-dependent apoptosis by facilitating calcium transport from the ER lumen to the mitochondria intermembrane space thus providing calcium for the downstream calcium channel MCU that directly releases it into mitochondria matrix. Mediates cytochrome c efflux. 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.

Subunit / interactions. Homodimer and homotrimer; in response to cyclic AMP or calcium; oligomerization is required for scramblase activity. Component of the mitochondrial permeability transition pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF. Interacts with SPG7, NIPSNAP2 and SLC25A30. Interacts with hexokinases including HK1. The HK1-VDAC1 complex interacts with ATF2. Interacts with BCL2L1. Interacts with BAK1. Interacts with RTL10/BOP (via BH3 domain). Interacts with amyloid-beta and APP; induces VDAC1 dephosphorylation. Interacts with TMEM41B. Interacts with BCAP31. Interacts with HSPA9; this interaction couples ITPR1 to VDAC1. (Microbial infection) Interacts with influenza A virus PB1-F2 protein.

Subcellular location. Mitochondrion outer membrane. Cell membrane. Membrane raft.

Tissue specificity. Expressed in erythrocytes (at protein level). Expressed in heart, liver and skeletal muscle.

Post-translational modifications. Phosphorylation at Ser-193 by NEK1 promotes the closed conformational state preventing excessive mitochondrial membrane permeability and subsequent apoptotic cell death after injury. Phosphorylation by the AKT-GSK3B axis stabilizes the protein probably by preventing ubiquitin-mediated proteasomal degradation. Ubiquitinated. Undergoes monoubiquitination and polyubiquitination by PRKN; monoubiquitination at Lys-274 inhibits apoptosis, whereas polyubiquitination leads to its degradation and promotes mitophagy. Deubiquitinated by USP30.

Activity regulation. Inhibited by nitric oxide.

Domain organisation. Consists mainly of a membrane-spanning beta-barrel formed by 19 beta-strands. The helical N-terminus folds back into the pore opening and plays a role in voltage-gated channel activity.

Similarity. Belongs to the eukaryotic mitochondrial porin family.

RefSeq proteins (20): NP_001387937, NP_001387938, NP_001387939, NP_001387940, NP_001387945, NP_001387946, NP_001387947, NP_001387949, NP_001387950, NP_001387951, NP_001387952, NP_001387953, NP_001387954, NP_001387955, NP_001387956, NP_001387957, NP_001387958, NP_001387960, NP_001387961, NP_003365* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001925	Porin_Euk	Family
IPR023614	Porin_dom_sf	Homologous_superfamily
IPR027246	Porin_Euk/Tom40	Family

Pfam: PF01459

Catalyzed reactions (Rhea), 12 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• chloride(in) = chloride(out) (RHEA:29823)
• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• a 1,2-diacyl-sn-glycero-3-phosphocholine(in) = a 1,2-diacyl-sn-glycero-3-phosphocholine(out) (RHEA:38571)
• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) (RHEA:38663)
• L-glutamate(out) = L-glutamate(in) (RHEA:66336)
• dopamine(out) = dopamine(in) (RHEA:73863)
• acetylcholine(in) = acetylcholine(out) (RHEA:74663)
• ATP(in) = ATP(out) (RHEA:75687)
• Fe(III)-cytochrome c = Fe(III)-cytochrome c (RHEA:79311)

UniProt features (96 total): strand 23, transmembrane region 19, modified residue 12, cross-link 9, turn 9, binding site 8, mutagenesis site 8, short sequence motif 2, helix 2, initiator methionine 1, chain 1, site 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6G6U	X-RAY DIFFRACTION	2.74
5XDO	X-RAY DIFFRACTION	3.1
5XDN	X-RAY DIFFRACTION	3.15
6G73	X-RAY DIFFRACTION	3.27
8J0O	ELECTRON MICROSCOPY	3.32
2JK4	X-RAY DIFFRACTION	4.1
9PFZ	ELECTRON MICROSCOPY	5.4
2K4T	SOLUTION NMR
5JDP	SOLUTION NMR
6TIQ	SOLUTION NMR
6TIR	SOLUTION NMR
7QI2	SOLID-STATE NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21796-F1	93.19	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 73 (involved in ceramide and phosphatidylcholine binding. critical for channel structural stability and gating)

Ligand- & substrate-binding residues (8): 12; 20; 242; 243; 244; 261; 263; 264

Post-translational modifications (21): 2, 13, 19, 20, 20, 67, 107, 109, 193, 240, 252, 266, 12, 20, 53, 61, 109, 110, 161, 266 …

Mutagenesis-validated functional residues (8):

Position	Phenotype
12	prkn-dependent polybiquitination is decreased, whereas prkn-dependent monoubiquitination, mitochondrial calcium uptake a
20	prkn-dependent polybiquitination is decreased, whereas prkn-dependent monoubiquitination, mitochondrial calcium uptake a
53	prkn-dependent polybiquitination is decreased, whereas prkn-dependent monoubiquitination, mitochondrial calcium uptake a
73	abolishes ceramide and phosphatidylcholine binding.
109–110	prkn-dependent polybiquitination is decreased, whereas prkn-dependent monoubiquitination, mitochondrial calcium uptake a
193	conformation remains open and constitutively allows cytochrome c efflux.
193	conformation remains closed and prevents cytochrome c leakage.
274	loss of prkn-dependent monoubiquitination increases mitochondria calcium uptake, and ultimately increased apoptosis. con

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5689880	Ub-specific processing proteases
R-HSA-70268	Pyruvate metabolism
R-HSA-8949215	Mitochondrial calcium ion transport

MSigDB gene sets: 387 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, MODY_HIPPOCAMPUS_POSTNATAL, GOBP_COGNITION, MORF_ESPL1, GOBP_BEHAVIOR, MORF_BUB1, MODULE_151, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, MORF_RRM1, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE

GO Biological Process (22): behavioral fear response (GO:0001662), monoatomic anion transport (GO:0006820), lipid transport (GO:0006869), apoptotic process (GO:0006915), neuron-neuron synaptic transmission (GO:0007270), learning (GO:0007612), epithelial cell differentiation (GO:0030855), calcium import into the mitochondrion (GO:0036444), pyruvate biosynthetic process (GO:0042866), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), negative regulation of calcium import into the mitochondrion (GO:0110099), positive regulation of mitophagy (GO:1901526), regulation of autophagy of mitochondrion (GO:1903146), positive regulation of type 2 mitophagy (GO:1905091), mitochondrial transmembrane transport (GO:1990542), negative regulation of reactive oxygen species metabolic process (GO:2000378), monoatomic ion transport (GO:0006811), chemical synaptic transmission (GO:0007268), transmembrane transport (GO:0055085), monoatomic anion transmembrane transport (GO:0098656), regulation of mitophagy (GO:1901524)

GO Molecular Function (14): voltage-gated monoatomic ion channel activity (GO:0005244), ATP binding (GO:0005524), oxysterol binding (GO:0008142), voltage-gated monoatomic anion channel activity (GO:0008308), porin activity (GO:0015288), cholesterol binding (GO:0015485), protein kinase binding (GO:0019901), phosphatidylcholine binding (GO:0031210), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), ceramide binding (GO:0097001), nucleotide binding (GO:0000166), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (12): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial permeability transition pore complex (GO:0005757), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondrial membrane (GO:0031966), mitochondrial nucleoid (GO:0042645), membrane raft (GO:0045121), synapse (GO:0045202), pore complex (GO:0046930), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Protein localization	1
Mitophagy	1
Deubiquitination	1
Aerobic respiration and respiratory electron transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
apoptotic process	2
regulation of apoptotic process	2
sterol binding	2
protein binding	2
binding	2
intracellular membrane-bounded organelle	2
mitochondrial envelope	2
mitochondrion	2
behavioral defense response	1
fear response	1
monoatomic ion transport	1
lipid localization	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
chemical synaptic transmission	1
learning or memory	1
cell differentiation	1
epithelium development	1
mitochondrial calcium ion transmembrane transport	1
intercellular transport	1
pyruvate metabolic process	1
monocarboxylic acid biosynthetic process	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	1
calcium import into the mitochondrion	1
regulation of calcium import into the mitochondrion	1
negative regulation of calcium ion transmembrane transport	1
mitophagy	1
positive regulation of macroautophagy	1
regulation of mitophagy	1
positive regulation of autophagy of mitochondrion	1
autophagy of mitochondrion	1
regulation of autophagy	1
type 2 mitophagy	1
positive regulation of mitophagy	1
regulation of type 2 mitophagy	1
mitochondrial transport	1
transmembrane transport	1

Protein interactions and networks

STRING

4802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VDAC1	HSPA9	P30036	996
VDAC1	ITPR1	Q14643	996
VDAC1	ITPR3	Q14573	996
VDAC1	PPIF	P30405	995
VDAC1	BCL2L1	Q07817	995
VDAC1	BCL2	P10415	995
VDAC1	TSPO	P30536	995
VDAC1	HK1	P19367	984
VDAC1	HK2	P52789	980
VDAC1	MAPT	P10636	974
VDAC1	SNCA	P37840	972
VDAC1	MCL1	Q07820	961
VDAC1	FIS1	Q9Y3D6	959
VDAC1	STAR	P49675	958
VDAC1	ACBD3	Q9H3P7	955

IntAct

261 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
VDAC1	VDAC3	psi-mi:“MI:0915”(physical association)	0.670
VDAC1	VDAC1	psi-mi:“MI:0407”(direct interaction)	0.650
VP24	KPNA6	psi-mi:“MI:0914”(association)	0.620
VDAC1	VDAC2	psi-mi:“MI:0915”(physical association)	0.620
VDAC1	APOE	psi-mi:“MI:0915”(physical association)	0.590
PB1	VDAC1	psi-mi:“MI:0915”(physical association)	0.590
VDAC1	PB1	psi-mi:“MI:0915”(physical association)	0.590
ATF2	HK1	psi-mi:“MI:0915”(physical association)	0.580
HK1	ATF2	psi-mi:“MI:0915”(physical association)	0.580
VDAC1	HK1	psi-mi:“MI:0914”(association)	0.560
VDAC1	RTL10	psi-mi:“MI:0915”(physical association)	0.540
VDAC1	RTL10	psi-mi:“MI:0407”(direct interaction)	0.540
STOM	EI24	psi-mi:“MI:0914”(association)	0.510
VDAC1	PRDX6	psi-mi:“MI:0915”(physical association)	0.500
VDAC1	YWHAE	psi-mi:“MI:0915”(physical association)	0.500
VDAC1	CDK1	psi-mi:“MI:0915”(physical association)	0.500
	VDAC1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (717): VDAC1 (Affinity Capture-RNA), VDAC1 (Affinity Capture-RNA), VDAC1 (Affinity Capture-Western), VDAC1 (Affinity Capture-Western), VDAC1 (Affinity Capture-MS), VDAC1 (Affinity Capture-MS), APOE (Affinity Capture-MS), ZG16B (Affinity Capture-MS), HAL (Affinity Capture-MS), VDAC1 (Affinity Capture-MS), ATP5A1 (Co-fractionation), ATP5B (Co-fractionation), ATP5D (Co-fractionation), ATP5I (Co-fractionation), ATP5O (Co-fractionation)

ESM2 similar proteins: A0A1S4A695, A0A6P7EFR0, A4F267, A6QR22, O97556, P07144, P21796, P42055, P42056, P45879, P45880, P50395, P50397, P50399, P62495, P62496, P62497, P62498, P68002, P68003, P81004, P81155, P82013, P86223, Q0VCK5, Q0VCX5, Q1W374, Q1W375, Q1W376, Q1W377, Q29380, Q5R4C7, Q5R7V4, Q5RCE1, Q5U2Q7, Q60930, Q60931, Q60932, Q61598, Q6Q7J2

Diamond homologs: A0A6P7EFR0, P07144, P21796, P45879, P45880, P68002, P68003, P81004, P81155, P82013, P82945, P83781, P86223, Q21752, Q29380, Q5R7V4, Q60930, Q60931, Q60932, Q94920, Q9MZ13, Q9MZ15, Q9MZ16, Q9R1Z0, Q9TT13, Q9TT15, Q9Y277, Q9Z2L0, P04840, P40478, Q9P544, Q7F4F8

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NEK1	down-regulates	VDAC1	phosphorylation
FAM162A	“up-regulates activity”	VDAC1	binding
TSPO2	“up-regulates activity”	VDAC1	binding
SGK1	“down-regulates quantity”	VDAC1	phosphorylation
SOD1	“down-regulates activity”	VDAC1	binding
BAX	“up-regulates activity”	VDAC1	binding
BCL2L1	“down-regulates activity”	VDAC1	binding
VDAC1	up-regulates	Apoptosis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 212 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TRAF6 mediated NF-kB activation	5	15.3×	3e-03
TAK1-dependent IKK and NF-kappa-B activation	6	12.1×	3e-03
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	5	12.0×	5e-03
NOD1/2 Signaling Pathway	5	10.7×	5e-03
RHOH GTPase cycle	5	10.4×	5e-03
Plasma lipoprotein assembly, remodeling, and clearance	6	9.2×	5e-03
Signaling by VEGF	6	8.8×	5e-03
Leishmania infection	7	7.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mitochondrial membrane potential	5	14.8×	5e-03
canonical NF-kappaB signal transduction	6	11.9×	4e-03
positive regulation of type I interferon production	5	11.4×	1e-02
JNK cascade	6	8.9×	9e-03
endocytosis	12	6.2×	8e-04
positive regulation of canonical NF-kappaB signal transduction	12	4.7×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

38 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1231 predictions. Top by Δscore:

Variant	Effect	Δscore
5:133972861:ACCT:A	acceptor_loss	1.0000
5:133972863:CT:C	acceptor_loss	1.0000
5:133973790:CCTGG:C	donor_gain	1.0000
5:133973849:C:CC	acceptor_gain	1.0000
5:133973850:T:A	acceptor_loss	1.0000
5:133975862:GATAC:G	donor_loss	1.0000
5:133975867:CCACC:C	donor_loss	1.0000
5:133975868:CAC:C	donor_loss	1.0000
5:133975869:A:AC	donor_gain	1.0000
5:133975870:C:CC	donor_gain	1.0000
5:133976017:CATTC:C	acceptor_gain	1.0000
5:133976018:ATTC:A	acceptor_gain	1.0000
5:133976019:TTC:T	acceptor_gain	1.0000
5:133976020:TC:T	acceptor_gain	1.0000
5:133976021:CC:C	acceptor_gain	1.0000
5:133976022:C:CC	acceptor_gain	1.0000
5:133976023:T:A	acceptor_loss	1.0000
5:133976029:C:CT	acceptor_gain	1.0000
5:133980725:TTAC:T	donor_loss	1.0000
5:133980726:TA:T	donor_loss	1.0000
5:133980727:A:AC	donor_gain	1.0000
5:133980727:A:AT	donor_loss	1.0000
5:133980728:C:CG	donor_gain	1.0000
5:133980728:CA:C	donor_gain	1.0000
5:133980728:CACA:C	donor_gain	1.0000
5:133980728:CACAT:C	donor_gain	1.0000
5:133980952:TTTTC:T	acceptor_gain	1.0000
5:133980953:TTTC:T	acceptor_gain	1.0000
5:133980954:TTC:T	acceptor_gain	1.0000
5:133980955:TC:T	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000019383 (5:133983859 G>A,T), RS1000025585 (5:134103080 G>A), RS1000030776 (5:134112306 T>C), RS1000072485 (5:134017386 G>C,T), RS1000081127 (5:134039610 T>G), RS1000096592 (5:133997430 G>A), RS1000103839 (5:133973384 A>T), RS1000147638 (5:134081165 G>A), RS1000148331 (5:134058981 A>G), RS1000169501 (5:133991200 T>C,G), RS1000170476 (5:133981064 G>A), RS1000188656 (5:134115246 AGC>A), RS1000244656 (5:134075630 C>A,G), RS1000256483 (5:134096909 T>C), RS1000269451 (5:133991851 A>G,T)

Disease associations

OMIM: gene MIM:604492 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004866_13	Alopecia areata	9.000000e-07
GCST005752_8	Systemic lupus erythematosus	7.000000e-07
GCST009391_2055	Metabolite levels	3.000000e-06
GCST009391_696	Metabolite levels	3.000000e-06
GCST009723_5	Vertical cup-disc ratio (adjusted for vertical disc diameter)	8.000000e-12
GCST009724_49	Vertical cup-disc ratio (multi-trait analysis)	7.000000e-12
GCST009724_50	Vertical cup-disc ratio (multi-trait analysis)	5.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010345	cholesteryl ester 18:2 measurement
EFO:0007745	lactate measurement
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295729 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.05	Kd	8.989	nM	CHEMBL3752910
8.05	ED50	8.989	nM	CHEMBL3752910
7.25	Kd	55.92	nM	CHEMBL5653589
7.25	ED50	55.92	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 13 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149760: Binding affinity to human VDAC1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0090	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149760: Binding affinity to human VDAC1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0559	uM

CTD chemical–gene interactions

96 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetylcysteine	decreases reaction, increases expression, affects binding, increases reaction, affects cotreatment (+1 more)	5
bisphenol A	decreases expression, decreases methylation, increases expression	3
Arsenic Trioxide	decreases reaction, increases reaction, increases expression, increases response to substance, affects cotreatment (+1 more)	3
Hydrogen Peroxide	affects binding, decreases reaction, increases reaction, increases expression	3
bisphenol F	decreases expression, increases expression, affects cotreatment	2
trichostatin A	affects cotreatment, increases expression	2
sodium arsenite	decreases expression, increases expression	2
chromium hexavalent ion	decreases reaction, increases expression, affects expression, decreases abundance	2
Cisplatin	increases expression, increases response to substance, decreases expression	2
Doxorubicin	decreases expression, decreases reaction, affects reaction	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	increases methylation, decreases expression	2
1-Methyl-4-phenylpyridinium	affects expression, increases expression	2
ME-344	affects binding, affects response to substance, affects localization, decreases reaction, increases abundance	1
FR900359	increases phosphorylation	1
PF-06840003	decreases expression, decreases reaction	1
3-monochloropropane-1, 2 diol ester	increases expression, decreases reaction	1
lead acetate	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases degradation, increases reaction, affects cotreatment, decreases reaction	1
asiatic acid	decreases reaction, increases expression	1
salvin	decreases ubiquitination, affects reaction, decreases expression, decreases reaction	1
ochratoxin A	decreases expression	1
gossypol acetic acid	affects reaction, decreases expression	1
aflatoxin B2	decreases methylation	1
diallyl trisulfide	decreases expression	1
fosbretabulin	decreases reaction, affects binding	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	increases expression	1
efavirenz	affects binding, increases reaction	1
chloropicrin	affects expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4261456	Binding	Binding affinity to VDAC1 in HUVEC assessed as AMPK phosphorylation at Thr172 residue after 24 hrs by Western blot analysis	Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3L6	Abcam HEK293T VDAC1 KO	Transformed cell line	Female
CVCL_E0SR	Ubigene HeLa VDAC1 KO	Cancer cell line	Female
CVCL_TX37	HAP1 VDAC1 (-) 1	Cancer cell line	Male
CVCL_XU97	HAP1 VDAC1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.