The reference OMIM entry for this protein is 610029
Voltage-dependent anion channel 3; vdac3
DESCRIPTION
VDAC3 belongs to a group of mitochondrial membrane channels involved in translocation of adenine nucleotides through the outer membrane. These channels may also function as a mitochondrial binding site for hexokinase (see HK1;
142600) and glycerol kinase (GK;
300474) (Rahmani et al., 1998).
CLONING
By PCR of a human liver cDNA library, Rahmani et al. (1998) cloned VDAC3. The deduced 283-amino acid protein is 67% identical to VDAC1 (
604492) and 73% identical to VDAC2 (
193245). Northern blot analysis detected a 1.4-kb transcript in all tissues examined, with high expression in testis. SDS-PAGE of transfected COS-1 cells showed epitope-tagged VDAC3 at about 30 kD.
GENE FUNCTION
Yogoda et al. (2007) described the mechanism of action of the selective antitumor agent erastin, involving the RAS-RAF-MEK signaling pathway functioning in cell proliferation, differentiation, and survival. Erastin exhibits greater lethality in human tumor cells harboring mutations in the oncogenes HRAS (
190020), KRAS (
190070), or BRAF (
164757). Using affinity purification and mass spectrometry, Yogoda et al. (2007) discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs), a novel target for anticancer drugs. Yogoda et al. (2007) showed that erastin treatment of cells harboring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, nonapoptotic mechanism. RNA interference-mediated knockdown of VDAC2 (
193245) or VDAC3 caused resistance to erastin, implicating these 2 VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, Yogoda et al. (2007) found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabeled analog and a filter-binding assay, Yogoda et al. (2007) showed that erastin binds directly to VDAC2. Yogoda et al. (2007) concluded that ligands to VDAC proteins can induce nonapoptotic cell death selectively in some tumor cells harboring activating mutations in the RAS-RAF-MEK pathway.
MAPPING
Using FISH, Rahmani et al. (1998) mapped the VDAC3 gene to chromosome 8p11.2. They stated that the mouse Vdac3 gene maps to a proximal region of chromosome 8 that shares homology of synteny with human chromosome 8p.
ANIMAL MODEL
Sampson et al. (2001) found that Vdac3-null mice were born at the expected mendelian ratio. Mutant females were fertile, but males were not due to markedly reduced sperm motility. The majority of epididymal axonemes showed structural defects, most commonly loss of a single microtubule doublet at a conserved position within the axoneme. In testicular sperm, the defect was only rarely observed, suggesting that instability of a normally formed axoneme occurred during sperm maturation. In contrast, tracheal epithelial cilia showed no structural abnormalities, but there was a reduced number of ciliated cells. In skeletal muscle, mitochondria were abnormally shaped, and the activities of respiratory chain complex enzymes were reduced. Citrate synthase (CS;
118950) activity was unchanged, suggesting an absence of mitochondrial proliferation that commonly occurs in response to respiratory chain defects. Anflous-Pharayra et al. (2007) found that Vdac3 -/- mice were indistinguishable from wildtype. Soleus muscle from Vdac3 -/- mice showed normal hexokinase-2 (HK2;
601125) protein content and activity and ...
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Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 610029 was added.