VDAC2

Last updated
VDAC2
Identifiers
Aliases VDAC2 , POR, voltage dependent anion channel 2
External IDs OMIM: 193245; MGI: 106915; HomoloGene: 37765; GeneCards: VDAC2; OMA:VDAC2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7417

22334

Ensembl

ENSG00000165637

ENSMUSG00000021771

UniProt

P45880
Q5JSD1

Q60930

RefSeq (mRNA)

NM_011695

RefSeq (protein)

NP_035825

Location (UCSC) Chr 10: 75.21 – 75.23 Mb Chr 14: 21.88 – 21.9 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Voltage-dependent anion-selective channel protein 2 is a protein that in humans is encoded by the VDAC2 gene on chromosome 10. [5] [6] This protein is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms. [7] [8] [9] VDACs are generally involved in the regulation of cell metabolism, mitochondrial apoptosis, 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 to infectious bursal disease (IBD). [11]

Contents

Structure

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]

Function

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 the outer 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 the mitochondrial 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]

Clinical significance

The VDAC2 protein 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 and glycerol kinase. The VDAC is an important constituent in apoptotic signaling and oxidative 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 normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory 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 opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal 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 during ischemic preconditioning of the heart. [23] Although a large burst of reactive 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]

Interactions

VDAC2 has been shown to interact with:

See also

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Apoptosome</span> A protein complex involved in the cellular apoptotic process.

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail.

The mitochondrial permeability transition pore is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stroke. Opening allows increase in the permeability of the mitochondrial membranes to molecules of less than 1500 daltons in molecular weight. Induction of the permeability transition pore, mitochondrial membrane permeability transition, can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting.

<span class="mw-page-title-main">Apoptosis regulator BAX</span> Mammalian protein found in Homo sapiens

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein which in humans is encoded by the BAK1 gene on chromosome 6. It belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">Voltage-dependent anion channel</span> Class of porin ion channels in the outer mitochondrial membrane

Voltage-dependent anion channels, or mitochondrial porins, are a class of porin ion channel located on the outer mitochondrial membrane. There is debate as to whether or not this channel is expressed in the cell surface membrane.

<span class="mw-page-title-main">Bcl-2-like protein 1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 1 is a protein encoded in humans by the BCL2L1 gene. Through alternative splicing, the gene encodes both of the human proteins Bcl-xL and Bcl-xS.

<span class="mw-page-title-main">HK1</span> Mammalian protein found in Homo sapiens

Hexokinase-1 (HK1) is an enzyme that in humans is encoded by the HK1 gene on chromosome 10. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in five transcript variants which encode different isoforms, some of which are tissue-specific. Each isoform has a distinct N-terminus; the remainder of the protein is identical among all the isoforms. A sixth transcript variant has been described, but due to the presence of several stop codons, it is not thought to encode a protein. [provided by RefSeq, Apr 2009]

<span class="mw-page-title-main">KCNB1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

<span class="mw-page-title-main">VDAC1</span> Protein-coding gene in the species Homo sapiens

Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the VDAC1 gene located on chromosome 5. It forms an ion channel in the outer mitochondrial membrane (OMM) and also the outer cell membrane. In the OMM, it allows ATP to diffuse out of the mitochondria into the cytoplasm. In the cell membrane, it is involved in volume regulation. Within all eukaryotic cells, mitochondria are responsible for synthesis of ATP among other metabolite needed for cell survival. VDAC1 therefore allows for communication between the mitochondrion and the cell mediating the balance between cell metabolism and cell death. Besides metabolic permeation, VDAC1 also acts as a scaffold for proteins such as hexokinase that can in turn regulate metabolism.

<span class="mw-page-title-main">ENDOG</span> Protein-coding gene in the species Homo sapiens

Endonuclease G, mitochondrial is an enzyme that in humans is encoded by the ENDOG gene. This protein primarily participates in caspase-independent apoptosis via DNA degradation when translocating from the mitochondrion to nucleus under oxidative stress. As a result, EndoG has been implicated in cancer, aging, and neurodegenerative diseases such as Parkinson's disease (PD). Regulation of its expression levels thus holds potential to treat or ameliorate those conditions.

<span class="mw-page-title-main">ADP/ATP translocase 4</span> Protein-coding gene in the species Homo sapiens

ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.

<span class="mw-page-title-main">VDAC3</span> Protein-coding gene in the species Homo sapiens

Voltage-dependent anion-selective channel protein 3 (VDAC3) is a protein that in humans is encoded by the VDAC3 gene on chromosome 8. The protein encoded by this gene is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms. 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. Mutations in VDAC3 have been linked to male infertility, as well as Parkinson's disease.

<span class="mw-page-title-main">HK2</span>

Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. [provided by RefSeq, Apr 2009]

<span class="mw-page-title-main">Bcl-2 family</span>

The Bcl-2 family consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. The Bcl-2 family proteins consists of members that either promote or inhibit apoptosis, and control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. A total of 25 genes in the Bcl-2 family were identified by 2008.

Tryptophan-rich sensory proteins (TspO) are a family of proteins that are involved in transmembrane signalling. In either prokaryotes or mitochondria they are localized to the outer membrane, and have been shown to bind and transport dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway. They are associated with the major outer membrane porins and with the voltage-dependent anion channel.

<span class="mw-page-title-main">ADP/ATP translocase 2</span> Protein-coding gene in humans

ADP/ATP translocase 2 is a protein that in humans is encoded by the SLC25A5 gene on the X chromosome.

<span class="mw-page-title-main">FAM162A</span> Protein-coding gene in the species Homo sapiens

Human growth and transformation-dependent protein (HGTD-P), also called E2-induced gene 5 protein (E2IG5), is a protein that in humans is encoded by the FAM162A gene on chromosome 3. This protein promotes intrinsic apoptosis in response to hypoxia via interactions with hypoxia-inducible factor-1α (HIF-1α). As a result, it has been associated with cerebral ischemia, myocardial infarction, and various cancers.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021771 – Ensembl, May 2017
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  13. 1 2 3 4 5 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. PMC   3264341 . PMID   22114330.
  14. ↑ 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. Bibcode:2010FEBSL.584.1793D. doi: 10.1016/j.febslet.2010.02.049 . PMID   20184885. S2CID   3391282.
  15. 1 2 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. doi:10.1128/mcb.24.9.3918-3927.2004. PMC   387743 . PMID   15082785.
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  18. ↑ 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. PMC   3478317 . PMID   22935710.
  19. ↑ Majumder S, Fisk HA (Mar 2013). "VDAC3 and Mps1 negatively regulate ciliogenesis". Cell Cycle. 12 (5): 849–58. doi:10.4161/cc.23824. PMC   3610733 . PMID   23388454.
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