VDAC1

The most abundant protein of the outer mitochondrial membrane (OMM) — a 283-amino-acid voltage-gated anion channel that serves as the primary metabolic gateway between the mitochondrial intermembrane space (IMS) and the cytosol. VDAC1 conducts ATP, ADP, NADH, phosphate, and Ca2+ in its open state, coupling inner-membrane bioenergetics to cytosolic metabolism. It is also a convergence point for apoptotic and mitophagic signaling, but its precise mechanistic role in both is actively debated.

Identity

Field	Value
UniProt	P21796 (VDAC1_HUMAN; Swiss-Prot, manually reviewed)
NCBI Gene	7416
HGNC	12669
Gene symbol	VDAC1
Mouse ortholog	Vdac1 (one-to-one)
Length	283 amino acids (canonical human isoform)
Molecular weight	~31 kDa
Subcellular location	OMM (primary); also plasma membrane, ER-mitochondria contact sites

Naming note: “VDAC1” refers to the protein; no separate pathway page exists for the VDAC family. VDAC2 and VDAC3 are paralogs with distinct functions (see Paralogs section).

Structure

VDAC1 adopts a 19-strand β-barrel that spans the OMM. The outer barrel dimensions are approximately 3.5 × 3.1 nm (horizontal) × 4 nm (vertical); the inner pore at the orifice is approximately 2.7 × 2.4 nm (27 × 24 Å) narrowing to 2.7 × 1.4 nm at the center where the N-terminal helix partially occludes the channel, in its open state ¹². Three independent structural studies published in 2008 resolved the fold:

• NMR in detergent micelles (Hiller et al. 2008) — solution structure of human VDAC1 in LDAO micelles ³
• X-ray + NMR hybrid, human VDAC1 (Bayrhuber et al. 2008) — 4.0 Å X-ray resolution, conjoint NMR/X-ray structure determination ¹
• X-ray crystallography, mouse VDAC1 (Ujwal et al. 2008) — 2.3 Å resolution in lipidic bicelles; detailed metabolite-gating insights; all 283 aa resolved ²

A short N-terminal α-helix (residues ~1–26) folds into the pore lumen and acts as a voltage sensor / gating element: it partially occludes the channel at high membrane potentials (>30–40 mV), switching the channel from its open anion-selective state to a closed cation-selective state. At physiological OMM potentials (typically low, ~10–20 mV), VDAC1 resides predominantly in the open conformation.

Key PTMs relevant to channel function and protein–protein interactions:

• Ser193 phosphorylation by NEK1 — modulates VDAC1 closure; implicated in apoptotic regulation
• K27-linked polyubiquitination by parkin — mitophagy signal (see Parkin substrate role below)
• N-terminal acetylation (Ala2) — co-translational; function unclear

Paralogs: VDAC family

Paralog	Abundance	Key distinguishing feature
VDAC1	Most abundant (~25–30% of OMM protein mass)	Primary metabolic gateway; predominant isoform
VDAC2	Less abundant	Essential chaperone for BAK — VDAC2 keeps BAK inactive at OMM 4
VDAC3	Least abundant; less characterized	Possible role in mitochondrial redox sensing

VDAC2–BAK relationship: VDAC2 was shown to directly bind and suppress BAK at the OMM, preventing spontaneous BAK activation ⁴. Loss of VDAC2 allows BAK to adopt an active conformation even in the absence of BH3-only signals. This is a VDAC2-specific function — VDAC1 does not chaperone BAK equivalently.

Dimension	Status
VDAC2–BAK interaction conserved in humans?	yes (human cell lines studied)
Phenotype conserved in humans?	partial (no human VDAC2 KO; mouse KO is lethal)
Replicated in humans?	no (genetic evidence only from cancer cell contexts)

Function: metabolic gateway

In its predominant open state, VDAC1 is the principal route for:

• ATP/ADP exchange — import ADP for ATP synthase; export newly synthesized ATP to cytosol
• NADH shuttle — outer-membrane step in malate-aspartate shuttle for cytosolic NADH reoxidation
• Phosphate (Pi) — import for oxidative phosphorylation
• Ca2+ transfer — passes Ca2+ from cytosol into IMS at ER-mitochondria contact sites (MAMs), where VDAC1 interacts with IP3Rs

Loss of VDAC1 disrupts mitochondrial bioenergetics and Ca2+ signaling, though cells can partially compensate via VDAC2/VDAC3 in most contexts.

Role in apoptosis — the MAC controversy

Initial model: VDAC1 oligomers as the cytochrome c release pore

Early studies proposed that VDAC1 oligomerizes in response to apoptotic signals to form a “mitochondrial apoptosis-induced channel” (MAC) large enough (~4–6 nm) to release cytochrome c (~12 kDa) across the OMM. In this model, VDAC1 oligomers — potentially in complex with bax or bak — would constitute the pore-forming machinery of MOMP. Several lines of biochemical evidence supported VDAC1’s co-immunoprecipitation with BAX and an anti-apoptotic role for VDAC1-targeting compounds.

Counter-evidence: VDAC1/3 double KO MEFs — BAX/BAK still functional

Baines et al. 2007 generated Vdac1-null, Vdac3-null, and Vdac1/Vdac3 double-knockout mouse embryonic fibroblasts (MEFs) ⁵. Key findings:

• Double-KO MEFs underwent normal MOMP (cytochrome c release, caspase-3 cleavage, PARP cleavage, and cell death) in response to multiple apoptotic stimuli (staurosporine, TNFα, adenoviral Bax overexpression, tBid, and H₂O₂)
• VDAC1/3-null MEFs were, if anything, more sensitive than wild-type to Ca²⁺ overload-induced death; no protection was observed
• Mitochondrial permeability transition pore (mPTP) opening (measured by calcein-CoCl₂ fluorescence and mitochondrial swelling) was also unaffected by Vdac1/3 loss in MEFs
• Note: The paper demonstrated equivalent downstream apoptotic outputs (cytochrome c release, caspase cleavage, cell death); it did not directly measure BAX translocation to mitochondria or BAK activation as discrete steps

This directly falsified the model in which VDAC1 (or VDAC3) is the obligatory pore for cytochrome c release.

Dimension	Status
Pathway conserved in humans?	yes (BAX/BAK MOMP pathway conserved)
Phenotype conserved in humans?	yes (VDAC-independent MOMP documented in human cell lines)
Replicated in humans?	no (human VDAC1/3 DKO genetics not achieved in vivo)

Current consensus view

VDAC1 is not the obligatory cytochrome c release pore. BAX and BAK form the OMM pore directly via BAX/BAK homo-oligomers (see bax and bak pages). However, VDAC1 modulates the apoptotic response in multiple ways:

• Recruits pro-apoptotic proteins (hexokinase II displacement releases VDAC-bound HK-II → increases susceptibility to MOMP)
• Mediates anti-apoptotic BCL-2 family interactions at the OMM — bcl-xl binds VDAC1 to modulate ion flux, though the functional significance is debated (see bcl-xl)
• VDAC1 oligomers may still play a modulatory (not obligatory) role in amplifying apoptotic signaling in certain cell types

contradictory-evidence — The exact mechanism by which VDAC1 modulates (rather than executes) MOMP remains incompletely resolved.

Parkin substrate role and mitophagy

PINK1 accumulates on depolarized mitochondria and phosphorylates ubiquitin (Ser65) + parkin (Ser65 of Ubl domain), activating Parkin’s E3 ubiquitin ligase activity. Geisler et al. 2010 established that VDAC1 is among the first OMM proteins ubiquitinated upon mitochondrial depolarization ⁶:

• VDAC1 is ubiquitinated predominantly with K27-linked polyubiquitin chains (atypical linkage) — the study identified both K27 and K63 linkages on VDAC proteins
• Ubiquitinated VDAC1 recruits p62 (SQSTM1) to the mitochondrial surface
• p62 links ubiquitinated OMM cargo to the autophagosome machinery (via its LIR motif binding LC3), facilitating selective engulfment of damaged mitochondria
• VDAC1 (and VDAC2) silencing impaired PINK1/Parkin-dependent mitophagy, confirming that VDAC1 ubiquitination is functionally necessary — not merely correlative — in this model

Note: The Geisler 2010 K27-linkage claim on parkin.md is marked verified-partial; the VDAC1 as Parkin substrate claim was confirmed in the primary source PDF by a prior verification pass on the parkin page.

Dimension	Status
PINK1/Parkin/VDAC1 pathway conserved in humans?	yes (human cell line data; Parkin overexpression system)
Phenotype conserved in humans?	partial (no in vivo human mitophagy genetic data for VDAC1 specifically)
Replicated in humans?	in-progress (Parkinson’s disease genetics supports PINK1/Parkin; VDAC1 role not independently validated in patient tissue)

Aging relevance

Metabolic gateway bottleneck in aged mitochondria

VDAC1’s abundance (~25–30% of OMM protein mass) makes it a potential gatekeeper for the bioenergetic decline observed in aging. Aged mitochondria exhibit reduced membrane potential, altered cristae morphology, and impaired OXPHOS capacity (see mitochondrial-dysfunction). If VDAC1 conductance or gating properties shift with age — due to oxidative modification, altered lipid environment, or post-translational changes — this could impair ATP/ADP exchange and amplify the bioenergetic deficit. unsourced — direct evidence for age-associated changes in VDAC1 channel properties in human tissue is lacking.

VDAC1 oligomerization and Ca2+ dysregulation

Elevated VDAC1 oligomerization has been observed under conditions of elevated ROS and in neurodegenerative disease contexts (amyloid-beta interaction with VDAC1 documented in Alzheimer’s disease models). VDAC1 oligomers may form a large pore that releases mitochondrial DNA (mtDNA) into the cytosol, activating the cgas-sting-pathway and driving chronic-inflammation. This mechanism has been proposed in endothelial aging contexts needs-replication. needs-human-replication

Reduced VDAC-1 function extends lifespan in C. elegans

Adedoja et al. 2025 reported that reduced VDAC-1 function in C. elegans extends lifespan via activation of the mitochondrial unfolded protein response (mtUPR), requiring elements of the PeBoW ribosome biogenesis complex ⁷. needs-human-replication — C. elegans lifespan results require extensive validation before translation to mammalian biology; the mtUPR pathway is conserved but the VDAC1 regulatory axis is not established in mammals.

Dimension	Status
Pathway conserved in humans?	partial (mtUPR is conserved; VDAC1 regulation of mtUPR is worm-specific so far)
Phenotype conserved in humans?	unknown
Replicated in humans?	no

Cancer overexpression (Warburg context)

VDAC1 is overexpressed in multiple cancer types, consistent with the Warburg effect: cancer cells upregulate glycolysis and require high-capacity ATP/ADP exchange through VDAC1. Hexokinase II (HK-II) binding to VDAC1 couples glycolysis to mitochondrial ATP production and simultaneously suppresses MOMP (anti-apoptotic). This pro-survival interaction makes the VDAC1-HK-II interface a cancer drug target, though this is orthogonal to aging per se. unsourced

Pathway membership

• mitophagy — Parkin substrate; ubiquitinated VDAC1 recruits p62 → autophagosome
• apoptosis-pathway — OMM component; modulates (not executes) BAX/BAK MOMP
• mitochondrial-dysfunction — primary OMM metabolic gateway; bioenergetic relevance in aging
• pink1-parkin-pathway — upstream kinase PINK1 activates Parkin → VDAC1 ubiquitination cascade

Key interactors

Protein	Nature of interaction	Functional consequence
parkin	E3 ubiquitin ligase → VDAC1 (substrate)	K27-polyUb; mitophagy signal 6
pink1	Upstream kinase activating Parkin	Indirect: depolarization → PINK1 → Parkin → VDAC1 Ub
p62	Adaptor binding polyUb-VDAC1	Bridges ubiquitinated OMM cargo to autophagosome
bak	VDAC2-specific chaperone client (NOT VDAC1)	VDAC2 keeps BAK inactive; loss of VDAC2 → BAK activation 4
bax	Reported co-IP at OMM	Disputed functional significance post-Baines 2007
bcl-xl	Reported VDAC1 binding; disputed	Proposed to modulate ion flux; mechanism contested; see bcl-xl
Hexokinase II	Physical OMM binding via N-terminal domain	Couples glycolysis to OXPHOS; suppresses MOMP

Pharmacology

No clinically approved VDAC1-targeting drug exists. Investigational approaches:

• DIDS (4,4’-diisothiocyanatostilbene-2,2’-disulfonic acid) — VDAC channel blocker; disrupts VDAC1-HK-II interaction; pro-apoptotic in cancer cell lines; non-specific (also blocks other anion channels); not clinically developed
• NADH analogs — some bind VDAC1 pore and modulate conductance; research tools only
• siRNA / antisense approaches targeting VDAC1 — explored in cancer; no aging-specific therapeutic program
• Erastin — VDAC2/3 modulator (not VDAC1-selective); disrupts system xCT/VDAC2 interaction; triggers ferroptosis; unrelated to VDAC1 aging biology

dose-response-unclear — no dose-response data for any VDAC1-targeted intervention in aging models.

Limitations and gaps

• unsourced — Direct evidence for age-dependent changes in VDAC1 channel conductance or PTM landscape in aged human tissue.
• needs-human-replication — VDAC-1 reduction → lifespan extension established only in C. elegans (Adedoja 2025); not replicated in mammalian models.
• needs-replication — VDAC1 oligomerization → mtDNA release → cGAS/STING activation in aging endothelium (single-study report, 2026).
• contradictory-evidence — VDAC1 role in MOMP: original MAC model vs. VDAC-dispensable Baines 2007 DKO result; current modulatory view incompletely mechanized.
• no-mechanism — How K27-linked vs K63-linked polyubiquitin on VDAC1 differentially direct cargo to autophagosome vs proteasome.
• needs-canonical-id — VDAC1 not in GenAge human subset; GenAge ID unknown.
• no-fulltext-access — Cheng 2003 (doi:10.1126/science.1083995): closed-access (not_oa); VDAC2–BAK chaperone claims on this page are unverified against the primary source.
• no-fulltext-access — Adedoja 2025 (doi:10.1101/gad.352979.125): download failed (HTTP 520 from publisher); diamond OA but not currently fetchable; C. elegans lifespan/mtUPR claims on this page are unverified against the primary source.
• no-fulltext-access — Hiller 2008 (doi:10.1126/science.1161302): no OA URL available; NMR-specific structural claims not independently verified (structural details cross-checked via Bayrhuber 2008 and Ujwal 2008 citations of Hiller’s work).

Footnotes

Footnotes

1. bayrhuber-2008-vdac1-crystal · doi:10.1073/pnas.0808115105 · in-vitro structural (X-ray + NMR hybrid, 4.0 Å X-ray resolution) · model: human VDAC1 refolded in E. coli · 19-strand β-barrel confirmed; outer barrel 3.5 × 3.1 nm × 4 nm; inner pore ≈1.5 × 1 nm; N-terminal helix Tyr7–Val17 folded inside barrel at midpoint ↩ ↩²

2. ujwal-2008-vdac1-crystal-mouse · doi:10.1073/pnas.0809634105 · in-vitro structural (X-ray 2.3 Å, bicelle crystallization) · model: mouse VDAC1; all 283 aa resolved + 47 water molecules · Rfree 27.7%, Rwork 24.2% · inner pore 27 × 24 Å at orifice, narrowing to 27 × 14 Å at N-terminal helix; N-terminal segment aa 1–26 resolved; helix aa 6–20; hinge Gly21–Gly25; metabolite-gating mechanism ↩ ↩²

3. hiller-2008-vdac1-nmr · doi:10.1126/science.1161302 · in-vitro structural (NMR) · model: human VDAC1 in LDAO micelles · 19-strand β-barrel architecture; N-terminal helix voltage sensor · no-fulltext-access — no OA URL available in archive; PDF not downloaded; structural details for Hiller-derived claims sourced from Bayrhuber 2008 and Ujwal 2008 cross-references ↩

4. cheng-2003-vdac2-bak · doi:10.1126/science.1083995 · in-vitro + in-vivo · n=814 cited · model: HEK293 cells, MEFs · VDAC2 physically chaperones BAK at OMM; loss-of-function allows spontaneous BAK activation; VDAC1 does not rescue ↩ ↩² ↩³

5. baines-2007-vdac-dispensable · doi:10.1038/ncb1575 · in-vivo/in-vitro (genetic KO + MEFs) · model: Vdac1-/-, Vdac3-/-, Vdac1/3-DKO mouse MEFs (E13.5–15.5); also isolated cardiac/liver mitochondria · stimuli: Ca²⁺ (100–250 µM), tBH (100 µM), recombinant Bax (1 µg), tBid (0.25 µg), staurosporine (300 nM), TNFα (3 ng/ml) · cytochrome c release, caspase-3/PARP cleavage, and MPT (calcein-CoCl₂) all unaffected by Vdac1/3 loss; DKO MEFs showed enhanced death at some stimuli; LOCAL PDF available ↩

6. geisler-2010-parkin-vdac1-mitophagy · doi:10.1038/ncb2012 · in-vitro (human cell lines, Parkin overexpression) · VDAC1/2 ubiquitinated by Parkin with K27/K63 polyUb; required for p62 recruitment and mitophagy flux; LOCAL PDF available · claim verified on parkin (verified-partial, 2026-05-04) ↩ ↩²

7. adedoja-2025-vdac1-lifespan-mtUPR · doi:10.1101/gad.352979.125 · in-vivo (C. elegans) · n=not-extracted · reduced VDAC-1 function extends lifespan via mtUPR activation; PeBoW complex required · no-fulltext-access — download failed (HTTP 520; publisher redirect); diamond OA but not currently fetchable · needs-human-replication ↩