Alternative titles; symbols
HGNC Approved Gene Symbol: VDAC1
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38) : 5:133,971,871-134,114,540 (from NCBI)
The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane is a small, abundant outer membrane pore-forming protein found in the outer membranes of all eukaryotic mitochondria. The VDAC protein is thought to form the major pathway for movement of adenine nucleotides through the outer membrane and to be the mitochondrial binding site for hexokinase (see 142600) and glycerol kinase (GK; 300474) (summary by Blachly-Dyson et al., 1993). At low transmembrane voltage, VDAC is open for anions such as phosphate, chloride, and adenine nucleotides. At higher transmembrane voltage, VDAC functions as a selective channel for cations and uncharged molecules. These features make VDAC likely to play a role in mitochondrial energy metabolism (summary by Huizing et al., 1996).
Blachly-Dyson et al. (1993) identified and characterized 2 human cDNAs encoding VDAC homologs, which they called HVDAC1 and HVDAC2 (VDAC2; 193245). Each human cDNA was expressed in essentially all human cell lines and tissues examined.
Huizing et al. (1998) studied by Northern and Western blot analyses the human tissue distribution of mitochondrial transmembrane metabolite carriers. They found that VDAC1 mRNA has a ubiquitous distribution, with most pronounced expression in heart, liver, and skeletal muscle, whereas the VDAC2 (193245) isoform appears to be expressed only in the heart.
Messina et al. (2000) determined that the VDAC1 gene contains 9 exons and spans about 33 kb. The first exon is noncoding. The promoter region lacks a canonical TATA box, but it is GC rich and has a sterol repressor element and binding sites for SRY (480000) and NRF2 (NFE2L2; 600492).
Blachly-Dyson et al. (1994) had mapped the VDAC1 to chromosome Xq13-q21; however, screening the human chromosome X cosmid library by Messina et al. (1999) resulted in the isolation only of processed pseudogenes, finely mapped to Xq22 and Xp11.2. By fluorescence in situ hybridization of a pool of 3 probes designed to VDAC1, Messina et al. (1999) mapped the VDAC1 gene to chromosome 5q31. The homologous mouse gene resides on proximal chromosome 11, in a region showing homology of synteny with human 5q31.
Blachly-Dyson et al. (1993) found that mitochondria expressing VDAC1 were capable of specifically binding hexokinase, whereas mitochondria expressing VDAC2 only bound hexokinase at background levels. They expressed the 2 human VDAC isoforms in yeast lacking the endogenous VDAC gene. The human proteins isolated from yeast mitochondria formed channels with the characteristics expected of VDAC when incorporated into planar lipid bilayers. Furthermore, expression of the human proteins in the deficient strains complemented phenotypic defects associated with elimination of the endogenous yeast VDAC gene. The mutant of S. cerevisiae was known as omp2.
The existence of multiple genes encoding VDAC isoforms in mammals was not unexpected. Antibodies generated to VDAC1 purified from mitochondria appeared to crossreact immunocytochemically with the plasma membrane. Biochemical and physiologic studies had also suggested that VDAC-like proteins may be present in the plasma membrane. Lewis et al. (1994) used post-embedding immunolabeling to investigate the presence of VDAC in the semitendinosus muscle of the cane toad Bufo marinus and found labeling not only of the outer mitochondrial membrane but also of the sarcoplasmic reticulum, indicating the presence of a VDAC-like protein in the sarcoplasmic reticulum. Lewis et al. (1994) suggested that the various VDAC isoforms may differ in their subcellular localization or cell type and developmental expression pattern.
Bathori et al. (1999) used biochemical and electrophysiologic techniques to detect and characterize porin, or VDAC1, within isolated caveolae and caveolae-like domains. Porin purified from caveolae had molecular (i.e., immunologic reactivity and chromatographic behavior) and electrophysiologic properties indistinguishable from those of mitochondrial porin. Thus, Bathori et al. (1999) concluded that VDAC1 is able to be incorporated into both the plasma membrane and the mitochondrial outer membrane.
During transduction of an apoptotic signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases (see 147678). The BCL2 family of proteins, whose members may be antiapoptotic or proapoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis. Shimizu et al. (1999) created liposomes that carried the mitochondrial porin channel VDAC to show that the recombinant proapoptotic proteins Bax (600040) and Bak (600516) accelerate the opening of VDAC, whereas the antiapoptotic protein BCLXL (600039) closes VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by BCLXL. In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by BCLXL. Shimizu et al. (1999) concluded that the BCL2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.
Geisler et al. (2010) identified VDAC1 as a target for parkin (PARK2; 602544)-mediated polyubiquitination and mitophagy in mitochondria damaged by dissipation of the membrane potential. Parkinson disease (PD; 600116)-associated PARK2 mutations interrupted this process, suggesting a role for interference of mitophagy in the pathogenesis of Parkinson disease.
Using a human cell culture model of PD, Chaudhuri et al. (2016) showed that overexpression of microRNA-7 (MIR7; 615239) inhibited mitochondrial permeability transition pore formation, mitochondrial fragmentation and depolarization, cytochrome c release, reactive oxygen species generation, and release of mitochondrial calcium in response to neurotoxin through downregulation of VDAC1. Knockdown of VDAC1 led to a decrease in intracellular reactive oxygen species generation and protection against neurotoxin, similar to MIR7 overexpression. Chaudhuri et al. (2016) concluded that MIR7 accomplishes neuroprotection by improving mitochondrial health by targeting VDAC1.
Kim et al. (2019) found that oxidatively stressed mitochondria release short mtDNA fragments via pores formed by the voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane. Furthermore, the positively charged residues in the N-terminal domain of VDAC1 interact with mtDNA, promoting VDAC1 oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, interferon signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus (SLE). Kim et al. (2019) suggested that inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release.
Crystal Structure
Hiller et al. (2008) presented the nuclear magnetic resonance solutions structure of recombinant human VDAC1 reconstituted in detergent micelles. It forms a 19-stranded beta barrel with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion. In the presence of cholesterol, recombinant VDAC1 can form voltage-gated channels in phospholipid bilayers similar to those of the native protein. NMR measurements revealed the binding sites of VDAC1 for the BCL2 protein BCLXL, for reduced beta-nicotinamide adenine dinucleotide, and for cholesterol. BCLXL interacts with the VDAC barrel laterally at strands 17 and 18.
Anflous-Pharayra et al. (2007) found that Vdac1 -/- mice were viable and exhibited mild growth retardation. Soleus muscle from Vdac1 -/- mice showed reduced hexokinase-2 (HK2; 601125) protein content and activity and impaired glucose tolerance, but normal exercise tolerance, compared with wildtype.
Anflous-Pharayra, K., Cai, Z.-J., Craigen, W. J. VDAC1 serves as a mitochondrial binding site for hexokinase in oxidative muscles. Biochim. Biophys. Acta 1767: 136-142, 2007. [PubMed: 17207767] [Full Text: https://doi.org/10.1016/j.bbabio.2006.11.013]
Bathori, G., Parolini, I., Tombola, F., Szabo, I., Messina, A., Oliva, M., De Pinto, V., Lisanti, M., Sargiacomo, M., Zoratti, M. Porin is present in the plasma membrane where it is concentrated in caveolae and caveolae-related domains. J. Biol. Chem. 274: 29607-29612, 1999. [PubMed: 10514428] [Full Text: https://doi.org/10.1074/jbc.274.42.29607]
Blachly-Dyson, E., Baldini, A., Litt, M., McCabe, E. R. B., Forte, M. Human genes encoding the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane: mapping and identification of two new isoforms. Genomics 20: 62-67, 1994. [PubMed: 7517385] [Full Text: https://doi.org/10.1006/geno.1994.1127]
Blachly-Dyson, E., Zambronicz, E. B., Yu, W. H., Adams, V., McCabe, E. R. B., Adelman, J., Colombini, M., Forte, M. Cloning and functional expression in yeast of two human isoforms of the outer mitochondrial membrane channel, the voltage-dependent anion channel. J. Biol. Chem. 268: 1835-1841, 1993. [PubMed: 8420959]
Chaudhuri, A. D., Choi, D. C., Kabaria, S., Tran, A., Junn, E. MicroRNA-7 regulates the function of mitochondrial permeability transition pore by targeting VDAC1 expression. J. Biol. Chem. 291: 6483-6493, 2016. [PubMed: 26801612] [Full Text: https://doi.org/10.1074/jbc.M115.691352]
Geisler, S., Holmstrom, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., Springer, W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biol. 12: 119-131, 2010. [PubMed: 20098416] [Full Text: https://doi.org/10.1038/ncb2012]
Hiller, S., Garces, R. G., Malia, T. J., Orekhov, V. Y., Colombini, M., Wagner, G. Solution structure of the integral human membrane protein VDAC-1 in detergent micelles. Science 321: 1206-1210, 2008. [PubMed: 18755977] [Full Text: https://doi.org/10.1126/science.1161302]
Huizing, M., Ruitenbeek, W., Thinnes, F. P., DePinto, V., Wendel, U., Trijbels, F. J. M., Smit, L. M. E., Ter Laak, H. J., Van Den Heuvel, L. P. Deficiency of the voltage-dependent anion channel: a novel cause of mitochondriopathy. Pediat. Res. 39: 760-765, 1996. [PubMed: 8726225] [Full Text: https://doi.org/10.1203/00006450-199605000-00003]
Huizing, M., Ruitenbeek, W., van den Heuvel, L. P., Dolce, V., Iacobazzi, V., Smeitink, J. A. M., Palmieri, F., Trijbels, J. M. F. Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders. J. Bioenerg. Biomembr. 30: 277-284, 1998. [PubMed: 9733094] [Full Text: https://doi.org/10.1023/a:1020501021222]
Kim, J., Gupta, R., Blanco, L. P., Yang, S., Shteinfer-Kuzmine, A., Wang, K., Zhu, J., Yoon, H. E., Wang, X., Kerkhofs, M., Kang, H., Brown, A. L., Park, S.-J., Xu, X., Zandee van Rilland, E., Kim, M. K., Cohen, J. I., Kaplan, M. J., Shoshan-Barmatz, V., Chung, J. H. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science 366: 1531-1536, 2019. [PubMed: 31857488] [Full Text: https://doi.org/10.1126/science.aav4011]
Lewis, T. M., Roberts, M. L., Bretag, A. H. Immunolabelling for VDAC, the mitochondrial voltage-dependent anion channel, on sarcoplasmic reticulum from amphibian skeletal muscle. Neurosci. Lett. 181: 83-86, 1994. [PubMed: 7898777] [Full Text: https://doi.org/10.1016/0304-3940(94)90565-7]
Messina, A., Guarino, F., Oliva, M., van den Heuvel, L. P., Smeitink, J., De Pinto, V. Characterization of the human porin isoform 1 (HVDAC1) gene by amplification on the whole human genome: a tool for porin deficiency analysis. Biochem. Biophys. Res. Commun. 270: 787-792, 2000. [PubMed: 10772903] [Full Text: https://doi.org/10.1006/bbrc.2000.2487]
Messina, A., Oliva, M., Rosato, C., Huizing, M., Ruitenbeek, W., van den Heuvel, L. P., Forte, M., Rocchi, M., De Pinto, V. Mapping of the human voltage-dependent action channel isoforms 1 and 2 reconsidered. Biochem. Biophys. Res. Commun. 255: 707-710, 1999. [PubMed: 10049775] [Full Text: https://doi.org/10.1006/bbrc.1998.0136]
Shimizu, S., Narita, M., Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399: 483-487, 1999. Note: Erratum: Nature 407: 767 only, 2000. [PubMed: 10365962] [Full Text: https://doi.org/10.1038/20959]