Voltage-dependent anion-selective channel protein 2 is aprotein that in humans is encoded by theVDAC2gene on chromosome 10.[5][6] This protein is avoltage-dependent anion channel and shares high structural homology with the other VDAC isoforms.[7][8][9] VDACs are generally involved in the regulation of cellmetabolism,mitochondrialapoptosis, and spermatogenesis.[10][11][12][13] Additionally, VDAC2 participates in cardiac contractions and pulmonary circulation, which implicate it in cardiopulmonary diseases.[10][11] VDAC2 also mediates immune response toinfectious bursal disease (IBD).[11]
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 VDAC2 isoform contains an abundance of cysteines, which allow for the formation of disulfide bridges and, ultimately, affect the flexibility of the β-barrel. VDACs also contain a mitochondrial targeting sequence for the protein's translocation to the outer mitochondrial membrane.[14] In particular, VDAC2 possesses an N-terminal longer by 11 residues compared to the other two isoforms.[9]
VDAC2 belongs to the mitochondrial porin family and is expected to share similar biological functions to the other VDAC isoforms. VDACs generally are involved in cellular energy metabolism by transporting ATP and other small ions and metabolites across theouter mitochondrial membrane.[10][11] In mammalian cardiomyocytes, VDAC2 promotes mitochondrial transport of calcium ions in order to power cardiac contractions.[10]
In addition, VDACs form part of themitochondrial permeability transition pore (MPTP) and, thus, facilitate cytochrome C release, leading to apoptosis.[10][15] 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][13][15] VDAC2 in particular has demonstrated a protective effect in cells undergoing mitochondrial apoptosis, and may even confer protection during aging.[16][17]
Furthermore, VDAcs have been linked to spermatogenesis, sperm maturation, motility, and fertilization.[13] Though all VDAC isoforms are ubiquitously expressed, VDAC2 is majorly found in the sperm outer dense fiber (ODF), where it is hypothesized to promote proper assembly and maintenance of sperm flagella.[18][19] It also localizes to the acrosomal membrane of the sperm, where it putatively mediates calcium ion transmembrane transport.[20]
The VDAC2 protein belongs to a group of mitochondrial membrane channels involved in translocation ofadenine nucleotides through the outer membrane. These channels may also function as a mitochondrial binding site forhexokinase andglycerol kinase. The VDAC is an important constituent in apoptotic signaling andoxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling.[21] Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis.Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normalembryologic processes, or during cell injury (such as ischemia-reperfusion injury duringheart attacks andstrokes) or during developments and processes incancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of theDNA andnucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed byphagocytes, thereby preventing aninflammatory response.[22] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role oppositemitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which containnuclear and orcytoplasmic elements. The ultrastructural appearance ofnecrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in manyphysiological andpathological processes. It plays an important role duringembryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
The VDAC2 protein has been implicated in cardioprotection against ischemia-reperfusion injury, such as duringischemic preconditioning of the heart.[23] Although a large burst ofreactive oxygen species (ROS) is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even been observed that during this release of reactive oxygen species, VDAC2 plays an important role in the mitochondrial cell death pathway transduction hereby regulating apoptotic signaling and cell death.
The VDAC2 protein has been linked persistent pulmonary hypertension of the newborn (PPHN), which causes a large majority of neonatal morbidity and mortality, due to its role as a major regulator of endothelium-dependent nitric oxide synthase (eNOS) in the pulmonary endothelium. eNOS has been attributed with regulating NOS activity in response to physiological stimuli, which is vital to maintain NO production for proper blood circulation to the lungs. As a result, VDAC2 is significantly involved in pulmonary circulation and may become a therapeutic target for treating diseases such as pulmonary hypertension,[11]
VDAC2 may also serve an immune function, as it has been hypothesized to detect and induce apoptosis in cells infected by the IBD virus. IBD, the equivalent HIV in birds, can compromise their immune systems and even cause fatal injury to the lymphoid organ, Studies of this process indicate that VDAC2 interacts with the viral protein V5 to mediate cell death.[13]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Blachly-Dyson E, Baldini A, Litt M, McCabe ER, Forte M (Mar 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.PMID7517385.
^Messina A, Oliva M, Rosato C, Huizing M, Ruitenbeek W, van den Heuvel LP, Forte M, Rocchi M, De Pinto V (Feb 1999). "Mapping of the human Voltage-Dependent Anion Channel isoforms 1 and 2 reconsidered".Biochemical and Biophysical Research Communications.255 (3):707–10.doi:10.1006/bbrc.1998.0136.PMID10049775.
^abcdeSubedi 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.PMID21241999.
^Liem DA, Honda HM, Zhang J, Woo D, Ping P (Dec 2007). "Past and present course of cardioprotection against ischemia-reperfusion injury".Journal of Applied Physiology.103 (6):2129–36.doi:10.1152/japplphysiol.00383.2007.PMID17673563.S2CID24815784.
Valis K, Neubauerova J, Man P, Pompach P, Vohradsky J, Kovar J (Apr 2008). "VDAC2 and aldolase A identified as membrane proteins of K562 cells with increased expression under iron deprivation".Molecular and Cellular Biochemistry.311 (1–2):225–31.doi:10.1007/s11010-008-9712-x.PMID18278581.S2CID20774884.
Mannella CA (1998). "Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications".Journal of Structural Biology.121 (2):207–18.doi:10.1006/jsbi.1997.3954.PMID9615439.
Ahmed M, Forsberg J, Bergsten P (2005). "Protein profiling of human pancreatic islets by two-dimensional gel electrophoresis and mass spectrometry".Journal of Proteome Research.4 (3):931–40.doi:10.1021/pr050024a.PMID15952740.
Decker WK, Bowles KR, Schatte EC, Towbin JA, Craigen WJ (Oct 1999). "Revised fine mapping of the human voltage-dependent anion channel loci by radiation hybrid analysis".Mammalian Genome.10 (10):1041–2.doi:10.1007/s003359901158.PMID10501981.S2CID27663120.
Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007)."Large-scale mapping of human protein-protein interactions by mass spectrometry".Molecular Systems Biology.3 (1): 89.doi:10.1038/msb4100134.PMC1847948.PMID17353931.
