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Voltage-dependent anion channel 3
Symbols VDAC3 ; HD-VDAC3; VDAC-3
External IDs OMIM610029 MGI106922 HomoloGene36115 GeneCards: VDAC3 Gene
Species Human Mouse
Entrez 7419 22335
Ensembl ENSG00000078668 ENSMUSG00000008892
UniProt Q9Y277 Q60931
RefSeq (mRNA) NM_001135694 NM_001198998
RefSeq (protein) NP_001129166 NP_001185927
Location (UCSC) Chr 8:
42.39 – 42.41 Mb
Chr 8:
22.58 – 22.59 Mb
PubMed search [1] [2]

Voltage-dependent anion-selective channel protein 3 (VDAC3) is a protein that in humans is encoded by the VDAC3 gene on chromosome 8. [1][2] The protein encoded by this gene is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms.[1][2][3] Nonetheless, VDAC3 demonstrates limited pore-forming ability and, instead, interacts with other proteins to perform its biological functions, including sperm flagella assembly and centriole assembly.[4][5] Mutations in VDAC3 have been linked to male infertility, as well as Parkinson’s disease.[6][7]


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. The sequence of the VDAC3 isoform contains an abundance of cysteines, which allow for the formation of disulfide bridges and, ultimately, affect the flexibility of the β-barrel.[3] VDACs also contain a mitochondrial targeting sequence for the protein's translocation to the outer mitochondrial membrane.[8] VDAC3 still yet possesses multiple isoforms, including a full-length form and shorter form termed VDAC3b. This shorter form is predominantly expressed over the full-length form at cell centrosomes.[4]


VDAC3 belongs to the mitochondrial porin family and is expected to share similar biological functions to the other VDAC isoforms. VDACs are involved in cell metabolism by transporting ATP and other small metabolites across the outer mitochondrial membrane. In addition, VDACs form part of the mitochondrial permeability transition pore (MPTP) and, thus, facilitate cytochrome C release, leading to apoptosis.[9] 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.[10] Nonetheless, experiments reveal a lack of pore-forming ability in the VDAC3 isoform, suggesting that it may perform different biological functions.[6][11] Notably, though all VDAC isoforms are ubiquitously expressed, VDAC3 is majorly found in the sperm outer dense fiber (ODF), where it is hypothesized to promote proper assembly and maintenance of sperm flagella.[4][5] Because the ODF membranes are not likely to support pore formation, VDAC3 may interact with protein partners to carry out other functions in the ODF.[12] For instance, within cells, VDAC3 predominantly localizes to the centrosome and recruits Mps1 to regulate centriole assembly.[4][5] In the case of localization to the mitochondria, VDAC3 interaction with Mps1 instead leads to ciliary disassembly.[5]

Clinical Significance[edit]

As VDAC3 is a regulator of sperm motility, male mice missing VDAC3 result in infertility.[6] Mutations in VDAC3 are also associated with Parkinson’s disease, as VDAC3 has been observed to target Parkin to defective mitochondria to eliminate them by mitophagy. Failure to eliminate these mitochondria result in the accumulation of reactive oxygen species, the commonly attributed cause of Parkinson’s disease.[7]


VDAC3 has been shown to interact with:

See also[edit]


  1. ^ a b Mao M, Fu G, Wu JS, Zhang QH, Zhou J, Kan LX, Huang QH, He KL, Gu BW, Han ZG, Shen Y, Gu J, Yu YP, Xu SH, Wang YX, Chen SJ, Chen Z (Jul 1998). "Identification of genes expressed in human CD34(+) hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America 95 (14): 8175–80. doi:10.1073/pnas.95.14.8175. PMC 20949. PMID 9653160. 
  2. ^ a b Rahmani Z, Maunoury C, Siddiqui A (Nov 1998). "Isolation of a novel human voltage-dependent anion channel gene". European Journal of Human Genetics 6 (4): 337–40. doi:10.1038/sj.ejhg.5200198. PMID 9781040. 
  3. ^ a b 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. 
  4. ^ a b c d e Majumder S, Slabodnick M, Pike A, Marquardt J, Fisk HA (Oct 2012). "VDAC3 regulates centriole assembly by targeting Mps1 to centrosomes". Cell Cycle 11 (19): 3666–78. doi:10.4161/cc.21927. PMID 22935710. 
  5. ^ a b c d Majumder S, Fisk HA (Mar 2013). "VDAC3 and Mps1 negatively regulate ciliogenesis". Cell Cycle 12 (5): 849–58. doi:10.4161/cc.23824. PMID 23388454. 
  6. ^ 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. 
  7. ^ a b c 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. 
  8. ^ De Pinto V, Messina A, Lane DJ, Lawen A (May 2010). "Voltage-dependent anion-selective channel (VDAC) in the plasma membrane". FEBS Letters 584 (9): 1793–9. doi:10.1016/j.febslet.2010.02.049. PMID 20184885. 
  9. ^ "Entrez Gene: voltage-dependent anion channel 3". 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ Hinsch KD, De Pinto V, Aires VA, Schneider X, Messina A, Hinsch E (Apr 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 279 (15): 15281–8. doi:10.1074/jbc.M313433200. PMID 14739283. 

Further reading[edit]

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