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| Symbol | VDAC2 |
| Full Name | Voltage-Dependent Anion Channel 2 |
| Chromosome | 10q22.2 |
| NCBI Gene | 7417 |
| Ensembl | ENSG00000165637 |
| OMIM | 193245 |
| UniProt | P45880 |
| Diseases | [Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als) |
| Expression | Ubiquitous, high in brain, heart, skeletal muscle |
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Mitochondrial outer membrane channel
Regulates BAK-dependent [apoptosis](/entities/apoptosis)
mPTP component candidate |
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, VDAC2 has a unique anti-apoptotic function through direct sequestration of BAK, 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, Parkinson's, and ALS.
The protein encoded by VDAC2 is VDAC2 Protein. See the protein page for detailed structural and functional information.
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)
VDAC2 has a unique role in restraining apoptosis:
- VDAC2 directly binds and sequesters BAK in the MOM in an inactive conformation
- Apoptotic stimuli (BH3-only proteins like BID, BIM) displace BAK from VDAC2
- Released BAK oligomerizes with BAX, forming pores that cause MOMP
- MOMP releases cytochrome c, activating caspases and triggering apoptosis
- VDAC2 knockout sensitizes cells to apoptotic stimuli, particularly BAK-dependent apoptosis
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
VDAC2 dysfunction contributes to mitochondrial failure in AD:
- VDAC2 expression is altered in AD brain, with increased levels in vulnerable hippocampal neurons
- Amyloid-beta directly interacts with VDAC channels, blocking metabolite transport and disrupting mitochondrial bioenergetics
- Phosphorylated tau binds VDAC2, impairing mitochondrial membrane potential
- VDAC2-mediated mitochondrial calcium overload exacerbates amyloid-beta-induced neurotoxicity
- Disruption of MAM contacts (involving VDAC2-IP3R-GRP75) is an early feature of AD pathogenesis
In PD, VDAC2 intersects with mitophagy and apoptotic pathways:
- PINK1-mediated phosphorylation of VDAC1 (and likely VDAC2) recruits Parkin to damaged mitochondria for mitophagy
- VDAC2 monoubiquitination by Parkin is a signal for p62/SQSTM1-dependent mitophagy
- Loss of VDAC2's anti-apoptotic BAK sequestration sensitizes dopaminergic neurons to MPTP/rotenone toxicity
- Alpha-synuclein oligomers interact with VDACs, disrupting mitochondrial membrane integrity
- SOD1 mutant aggregates interact with VDAC channels on the MOM, inhibiting metabolite transport
- TDP-43 pathology affects mitochondrial dynamics and VDAC-dependent import pathways
- Motor neurons are particularly vulnerable to VDAC dysfunction due to extreme bioenergetic demands
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).