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Voltage-dependent anion channel 1
Protein VDAC1 PDB 2JK4.png
Rendering based on PDB 2JK4.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols VDAC1 ; PORIN; VDAC-1
External IDs OMIM604492 MGI106919 HomoloGene107244 GeneCards: VDAC1 Gene
RNA expression pattern
PBB GE VDAC1 212038 s at tn.png
PBB GE VDAC1 217140 s at tn.png
More reference expression data
Species Human Mouse
Entrez 7416 22333
Ensembl ENSG00000213585 ENSMUSG00000020402
UniProt P21796 Q60932
RefSeq (mRNA) NM_003374 NM_011694
RefSeq (protein) NP_003365 NP_035824
Location (UCSC) Chr 5:
133.97 – 134.01 Mb
Chr 11:
52.36 – 52.39 Mb
PubMed search [1] [2]

Voltage-dependent anion-selective channel protein 1 is a protein that in humans is encoded by the VDAC1 gene on chromosome 5.[1][2] This protein is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms, which are involved in the regulation of cell metabolism, mitochondrial apoptosis, and spermatogenesis.[3][4][5][6] In particular, VDAC1 is the major calcium ion transport channel and is implicated in cancer and Parkinson’s Disease (PD).[7][8]


The three VDAC isoforms in human are highly conserved, particularly with respect to their 3D structure. VDACs form a wide β-barrel structure, inside of which the N-terminal resides to partially close the pore.[9] For VDAC1, this barrel-like channel is composed of 19 amphipathic β-strands, and the end of the N-terminal contains α-helix segments. The N-terminal is proposed to as a gate to the pore via swinging motions facilitated by a short glycine-containing motif. Additionally, the N-terminal serves as a docking site for HK1 binding.[10]


VDAC1 belongs to the mitochondrial porin family and is expected to share similar biological functions to the other VDAC isoforms.[11] Of the three isoforms, VDAC1 is the main calcium ion transport channel and the most abundantly transcribed.[8][12] VDACs are involved in cell metabolism by transporting ATP and other small metabolites across the outer mitochondrial membrane (OMM). Of note, its role in transporting calcium ions allows the protein to regulate the TCA cycle and, by extension, reactive oxygen species (ROS) production.[7] In yeast cells, ROS accumulates in response to oxidative stress, which results in impaired mitochondrial function and a “petite” phenotype. However, petite yeast cells exhibit a longer lifespan than wildtype cells and indicate a protective function by VDAC1 in similar circumstances, such as aging.[10][12] In addition, VDACs form part of the mitochondrial permeability transition pore (MPTP) and, thus, facilitate cytochrome C release, leading to apoptosis. VDACs have also been observed to interact with pro- or antiapoptotic proteins, such as Bcl-2 family proteins and kinases, and so may contribute to apoptosis independently from the MPTP.[11]

Clinical Significance[edit]

VDAC1 has been implicated in cancer through its interactions with antiapoptotic Bcl-2 proteins, particularly Bcl-xl, and Mcl-1, which are overexpressed during cancer. These two Bcl-2 proteins interact with VDAC1 to regulate calcium ion transport across the OMM and, ultimately, ROS production. While high levels of ROS induce cell death, non-lethal levels interfere with signal transduction pathways that can then promote cell proliferation, migration, and invasion in cancer cells.[7] Moreover, VDAC1 overexpression has been associated with increased apoptotic response and anti-cancer drugs and treatment efficacy, further supporting VDAC1 as a therapeutic target for cancer treatment.[7][13]

VDAC1 function in calcium ion transport also involves the protein in neurodegenerative diseases. In PD, VDAC1 increases calcium ion levels within the mitochondria, resulting in increased mitochondrial permeability, disrupted mitochondrial membrane potential, elevated ROS production, cell death, and neuronal degeneraation.[8]


VDAC1 has been shown to interact with:

See also[edit]


  1. ^ Blachly-Dyson E, Baldini A, Litt M, McCabe ER, Forte M (July 1994). "Human genes encoding the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane: mapping and identification of two new isoforms". Genomics 20 (1): 62–7. doi:10.1006/geno.1994.1127. PMID 7517385. 
  2. ^ "Entrez Gene: VDAC1 voltage-dependent anion channel 1". 
  3. ^ Subedi KP, Kim JC, Kang M, Son MJ, Kim YS, Woo SH (Feb 2011). "Voltage-dependent anion channel 2 modulates resting Ca²+ sparks, but not action potential-induced Ca²+ signaling in cardiac myocytes". Cell Calcium 49 (2): 136–43. doi:10.1016/j.ceca.2010.12.004. PMID 21241999. 
  4. ^ a b Alvira CM, Umesh A, Husted C, Ying L, Hou Y, Lyu SC, Nowak J, Cornfield DN (Nov 2012). "Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production". American Journal of Respiratory Cell and Molecular Biology 47 (5): 669–78. doi:10.1165/rcmb.2011-0436OC. PMID 22842492. 
  5. ^ Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ (Jul 2003). "VDAC2 inhibits BAK activation and mitochondrial apoptosis". Science 301 (5632): 513–7. doi:10.1126/science.1083995. PMID 12881569. 
  6. ^ Li Z, Wang Y, Xue Y, Li X, Cao H, Zheng SJ (Feb 2012). "Critical role for voltage-dependent anion channel 2 in infectious bursal disease virus-induced apoptosis in host cells via interaction with VP5". Journal of Virology 86 (3): 1328–38. doi:10.1128/JVI.06104-11. PMID 22114330. 
  7. ^ a b c d e Huang H, Shah K, Bradbury NA, Li C, White C (23 October 2014). "Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation". Cell Death & Disease 5: e1482. doi:10.1038/cddis.2014.419. PMID 25341036. 
  8. ^ a b c Chu Y, Goldman JG, Kelly L, He Y, Waliczek T, Kordower JH (Sep 2014). "Abnormal alpha-synuclein reduces nigral voltage-dependent anion channel 1 in sporadic and experimental Parkinson's disease". Neurobiology of Disease 69: 1–14. doi:10.1016/j.nbd.2014.05.003. PMID 24825319. 
  9. ^ Amodeo GF, Scorciapino MA, Messina A, De Pinto V, Ceccarelli M (2014). "Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel". PloS One 9 (8): e103879. doi:10.1371/journal.pone.0103879. PMID 25084457. 
  10. ^ a b c Reina S, Palermo V, Guarnera A, Guarino F, Messina A, Mazzoni C, De Pinto V (Jul 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 584 (13): 2837–44. doi:10.1016/j.febslet.2010.04.066. PMID 20434446. 
  11. ^ a b Lee MJ, Kim JY, Suk K, Park JH (May 2004). "Identification of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway". Molecular and Cellular Biology 24 (9): 3918–27. PMID 15082785. 
  12. ^ a b De Pinto V, Guarino F, Guarnera A, Messina A, Reina S, Tomasello FM, Palermo V, Mazzoni C (2010). "Characterization of human VDAC isoforms: a peculiar function for VDAC3?". Biochimica Et Biophysica Acta 1797 (6-7): 1268–75. doi:10.1016/j.bbabio.2010.01.031. PMID 20138821. 
  13. ^ a b Weisthal S, Keinan N, Ben-Hail D, Arif T, Shoshan-Barmatz V (Oct 2014). "Ca(2+)-mediated regulation of VDAC1 expression levels is associated with cell death induction". Biochimica Et Biophysica Acta 1843 (10): 2270–81. doi:10.1016/j.bbamcr.2014.03.021. PMID 24704533. 
  14. ^ a b Weng C, Li Y, Xu D, Shi Y, Tang H (March 2005). "Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells". J. Biol. Chem. 280 (11): 10491–500. doi:10.1074/jbc.M412819200. PMID 15637055. 
  15. ^ a b Shi Y, Chen J, Weng C, Chen R, Zheng Y, Chen Q, Tang H (June 2003). "Identification of the protein-protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins". Biochem. Biophys. Res. Commun. 305 (4): 989–96. doi:10.1016/s0006-291x(03)00871-4. PMID 12767928. 
  16. ^ Shimizu S, Konishi A, Kodama T, Tsujimoto Y (March 2000). "BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3100–5. doi:10.1073/pnas.97.7.3100. PMC 16199. PMID 10737788. 
  17. ^ Shimizu S, Narita M, Tsujimoto Y (June 1999). "Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC". Nature 399 (6735): 483–7. doi:10.1038/20959. PMID 10365962. 
  18. ^ Schwarzer C, Barnikol-Watanabe S, Thinnes FP, Hilschmann N (September 2002). "Voltage-dependent anion-selective channel (VDAC) interacts with the dynein light chain Tctex1 and the heat-shock protein PBP74". Int. J. Biochem. Cell Biol. 34 (9): 1059–70. doi:10.1016/s1357-2725(02)00026-2. PMID 12009301. 
  19. ^ Kusano H, Shimizu S, Koya RC, Fujita H, Kamada S, Kuzumaki N, Tsujimoto Y (October 2000). "Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC". Oncogene 19 (42): 4807–14. doi:10.1038/sj.onc.1203868. PMID 11039896. 
  20. ^ Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P (May 2003). "Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria". Circ. Res. 92 (8): 873–80. doi:10.1161/01.RES.0000069215.36389.8D. PMC 3691672. PMID 12663490. 
  21. ^ Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L (Nov 2012). "Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy". The Journal of Biological Chemistry 287 (48): 40652–60. doi:10.1074/jbc.M112.419721. PMID 23060438. 

Further reading[edit]

External links[edit]