VDAC2 — Voltage-Dependent Anion Channel 2
<table class="infobox infobox-gene">
<tr><th class="infobox-header" colspan="2">VDAC2 — Voltage-Dependent Anion Channel 2</th></tr>
<tr><td class="label">Symbol</td><td><strong>VDAC2</strong></td></tr>
<tr><td class="label">Full Name</td><td>Voltage-Dependent Anion Channel 2</td></tr>
<tr><td class="label">Chromosome</td><td>10q22.2</td></tr> [@shoshanbarmatz2017]
<tr><td class="label">NCBI Gene</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/7417" target="_blank">7417</a></td></tr> [@israelson2010]
<tr><td class="label">Ensembl</td><td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165637" target="_blank">ENSG00000165637</a></td></tr>
<tr><td class="label">OMIM</td><td><a href="https://omim.org/entry/193245" target="_blank">193245</a></td></tr>
<tr><td class="label">UniProt</td><td><a href="https://www.uniprot.org/uniprot/P45880" target="_blank">P45880</a></td></tr>
<tr><td class="label">Diseases</td><td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als)</td></tr>
<tr><td class="label">Expression</td><td>Ubiquitous, high in brain, heart, skeletal muscle</td></tr>
<tr><th class="infobox-subheader" colspan="2">Key Features</th></tr>
<tr><td colspan="2" style="font-size:0.85em">Mitochondrial outer membrane channel<br>Regulates BAK-dependent [apoptosis](/entities/apoptosis)<br>mPTP component candidate</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>,
...VDAC2 — Voltage-Dependent Anion Channel 2
<table class="infobox infobox-gene">
<tr><th class="infobox-header" colspan="2">VDAC2 — Voltage-Dependent Anion Channel 2</th></tr>
<tr><td class="label">Symbol</td><td><strong>VDAC2</strong></td></tr>
<tr><td class="label">Full Name</td><td>Voltage-Dependent Anion Channel 2</td></tr>
<tr><td class="label">Chromosome</td><td>10q22.2</td></tr> [@shoshanbarmatz2017]
<tr><td class="label">NCBI Gene</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/7417" target="_blank">7417</a></td></tr> [@israelson2010]
<tr><td class="label">Ensembl</td><td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165637" target="_blank">ENSG00000165637</a></td></tr>
<tr><td class="label">OMIM</td><td><a href="https://omim.org/entry/193245" target="_blank">193245</a></td></tr>
<tr><td class="label">UniProt</td><td><a href="https://www.uniprot.org/uniprot/P45880" target="_blank">P45880</a></td></tr>
<tr><td class="label">Diseases</td><td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als)</td></tr>
<tr><td class="label">Expression</td><td>Ubiquitous, high in brain, heart, skeletal muscle</td></tr>
<tr><th class="infobox-subheader" colspan="2">Key Features</th></tr>
<tr><td colspan="2" style="font-size:0.85em">Mitochondrial outer membrane channel<br>Regulates BAK-dependent [apoptosis](/entities/apoptosis)<br>mPTP component candidate</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">138 edges</a></td>
</tr>
</table>
Overview
VDAC2 (Voltage-Dependent Anion Channel 2) encodes the second isoform of the voltage-dependent anion channel family, the most abundant proteins in the mitochondrial outer membrane (MOM). VDAC2 forms a beta-barrel pore that controls the flux of metabolites (ATP, ADP, NADH), ions (Ca2+, K+, Cl-), and small molecules between the cytoplasm and mitochondrial intermembrane space. Unlike [VDAC1](/genes/vdac1), VDAC2 has a unique anti-apoptotic function through direct sequestration of [BAK](/genes/bak1), preventing premature mitochondrial outer membrane permeabilization (MOMP).
In neurodegenerative diseases, VDAC2 dysfunction contributes to mitochondrial bioenergetic failure, calcium dysregulation, and aberrant apoptosis — hallmarks of neuronal death in [Alzheimer's](/diseases/alzheimers-disease), [Parkinson's](/diseases/parkinsons-disease), and [ALS](/diseases/als).
The protein encoded by VDAC2 is [VDAC2 Protein](/proteins/vdac2-protein). See the protein page for detailed structural and functional information.
Function
VDAC2 forms a voltage-gated channel in the MOM with key properties:
- Open state (low voltage): Conducts anions (ATP4-, ADP3-, Pi) and small metabolites, enabling oxidative phosphorylation
- Closed state (high voltage): Reduced anion permeability but increased cation selectivity
- Metabolite channeling: VDAC2 interacts with hexokinase, creatine kinase, and ANT (adenine nucleotide translocator) to facilitate efficient energy transfer
- Calcium transport: Mediates mitochondrial Ca2+ uptake from ER via the VDAC2-IP3R-GRP75 complex at mitochondria-associated ER membranes (MAMs)
Anti-Apoptotic Function
VDAC2 has a unique role in restraining apoptosis:
VDAC2 directly binds and sequesters [BAK](/genes/bak1) in the MOM in an inactive conformation
Apoptotic stimuli (BH3-only proteins like BID, BIM) displace BAK from VDAC2
Released BAK oligomerizes with [BAX](/genes/bax), forming pores that cause MOMP
MOMP releases cytochrome c, activating [caspases](/genes/casp3) and triggering apoptosis
VDAC2 knockout sensitizes cells to apoptotic stimuli, particularly BAK-dependent apoptosisMitochondrial Permeability Transition
VDAC2 is a candidate component of the mitochondrial permeability transition pore (mPTP):
- Interacts with cyclophilin D (PPIF) and ANT at contact sites
- mPTP opening causes mitochondrial swelling, membrane potential collapse, and cell death
- Relevant to excitotoxic and ischemic neuronal death in neurodegeneration
Disease Associations
Alzheimer's Disease
VDAC2 dysfunction contributes to mitochondrial failure in [AD](/diseases/alzheimers-disease):
- VDAC2 expression is altered in AD brain, with increased levels in vulnerable hippocampal [neurons](/entities/neurons)
- [Amyloid-beta](/proteins/amyloid-beta) directly interacts with VDAC channels, blocking metabolite transport and disrupting mitochondrial bioenergetics
- Phosphorylated [tau](/proteins/tau) binds VDAC2, impairing mitochondrial membrane potential
- VDAC2-mediated mitochondrial calcium overload exacerbates [amyloid-beta](/proteins/amyloid-beta)-induced neurotoxicity
- Disruption of MAM contacts (involving VDAC2-IP3R-GRP75) is an early feature of AD pathogenesis
Parkinson's Disease
In [PD](/diseases/parkinsons-disease), VDAC2 intersects with mitophagy and apoptotic pathways:
- [PINK1](/genes/pink1)-mediated phosphorylation of VDAC1 (and likely VDAC2) recruits [Parkin](/genes/prkn) to damaged mitochondria for mitophagy
- VDAC2 monoubiquitination by Parkin is a signal for p62/[SQSTM1](/genes/sqstm1)-dependent mitophagy
- Loss of VDAC2's anti-apoptotic BAK sequestration sensitizes dopaminergic neurons to MPTP/rotenone toxicity
- [Alpha-synuclein](/proteins/alpha-synuclein) oligomers interact with VDACs, disrupting mitochondrial membrane integrity
ALS
- [SOD1](/entities/sod1) mutant aggregates interact with VDAC channels on the MOM, inhibiting metabolite transport
- [TDP-43](/proteins/tdp-43) pathology affects mitochondrial dynamics and VDAC-dependent import pathways
- Motor neurons are particularly vulnerable to VDAC dysfunction due to extreme bioenergetic demands
Expression
VDAC2 is broadly expressed with enrichment in energy-demanding tissues:
- Brain: Cortical neurons, hippocampal pyramidal neurons, dopaminergic neurons of substantia nigra, motor neurons
- Heart: Cardiomyocytes (highest expression of all VDAC isoforms)
- Skeletal muscle: Type I (oxidative) fibers
- Liver: Hepatocytes
- Kidney: Proximal tubular cells
VDAC2 is the predominant isoform in embryonic tissues, consistent with its essential anti-apoptotic role in development (VDAC2 knockout is embryonic lethal in mice).
See Also
- [VDAC1](/genes/vdac1) — Major MOM channel, pro-apoptotic
- [BAK1](/genes/bak1) — Pro-apoptotic effector sequestered by VDAC2
- [BAX](/genes/bax) — Pro-apoptotic effector, BAK partner
- [PINK1](/genes/pink1) — Mitophagy kinase, phosphorylates VDACs
- [Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondrial-dysfunction) — Central pathogenic mechanism
- [Calcium Homeostasis](/mechanisms/calcium-homeostasis) — VDAC2-mediated mitochondrial Ca2+ uptake
External Links
- [NCBI Gene: VDAC2](https://www.ncbi.nlm.nih.gov/gene/7417)
- [UniProt: P45880](https://www.uniprot.org/uniprot/P45880)
- [GeneCards: VDAC2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=VDAC2)
- [OMIM: 193245](https://omim.org/entry/193245)
References
[Cheng et al., VDAC2 inhibits BAK activation and mitochondrial apoptosis (2003) (2003)](https://doi.org/10.1126/science.1083995)
[Rostovtseva et al., VDAC regulation of mitochondrial calcium transport and its role in cell life and death (2020) (2020)](https://doi.org/10.3389/fonc.2020.01697)
[Unknown, Manczak & Reddy, Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease (2012) (2012)](https://doi.org/10.1093/hmg/dds360)
[Sun et al., Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy (2012) (2012)](https://doi.org/10.1074/jbc.M112.346809)
[Shoshan-Barmatz et al., VDAC1 as a player in disease and as a drug target for neurodegeneration (2017) (2017)](https://doi.org/10.3389/fnins.2017.00642)
[Israelson et al., Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS (2010) (2010)](https://doi.org/10.1016/j.neuron.2010.09.033)Pathway Diagram
The following diagram shows the key molecular relationships involving VDAC2 — Voltage-Dependent Anion Channel 2 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)