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Showing SLC25A6 — ANT3 is a alias.

SLC25A6

ADP/ATP translocase 3 · UniProt P12236

Length
298 aa
Mass
32.9 kDa
Annotated
2026-06-10
23 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC25A6 (ANT3) is a mitochondrial inner-membrane ADP/ATP translocase whose conformational state controls the mitochondrial permeability transition pore (mPTP), positioning it as a central node governing cytochrome c release and cell survival (PMID:16060289, PMID:37182101). The recombinant human protein binds ADP together with the high-affinity inhibitors atractyloside and bongkrekic acid, establishing its conserved nucleotide-translocase ligand pharmacology (PMID:16060289). mPTP control is exerted through a network of binding partners that hold ANT3 in a closed conformation: mortalin (HSPA9) shields ANT3 from cyclophilin D under MEK-ERK signaling (PMID:32156782), MRPL12 stabilizes the pore under physiological conditions (PMID:37182101), and EFHD1 directly inhibits the ANT3 conformational change to prevent pore opening, with these effects pharmacologically dissectable using the conformation-locking agents carboxyatractyloside and bongkrekic acid (PMID:38795203). Loss of these restraining interactions drives ANT3 conformational change, mPTP opening, and apoptosis (PMID:37182101, PMID:38795203). ANT3 abundance is set by opposing post-translational modifications: SIRT3-mediated deacetylation enhances its stability (PMID:42260555), whereas SIAH1- and MRPL13-directed K48-linked ubiquitination promote its proteasomal degradation (PMID:41573684, PMID:40841355). Independently of pore gating, ANT3 binds the MICOS component MIC60 through residue Thr126, competitively displacing MIC19 to destabilize the MICOS complex and drive mitochondrial fragmentation and intrinsic apoptosis (PMID:42020360). Influenza PB1-F2 co-opts this axis by binding ANT3 to sensitize cells to mitochondrial permeabilization (PMID:16201016), and SLC25A6 dosage tunes cardiac repolarization upstream of KATP channels (PMID:37495650).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Establishing that the human ANT3 isoform retains canonical adenine-nucleotide translocase pharmacology was necessary to treat it as a bona fide ADP/ATP carrier rather than an uncharacterized paralog.

    Evidence His-tagged human ANT-3 expressed in insect cell mitochondria, radioiodinated atractyloside binding and ADP/BKA competition versus bovine heart mitochondria

    PMID:16060289

    Open questions at the time
    • No structural model of the human isoform
    • Transport kinetics in a defined reconstituted system not reported
    • Does not address mPTP gating role
  2. 2005 High

    The discovery that influenza PB1-F2 physically binds ANT3 (and VDAC1) linked the translocase to virally driven mitochondrial permeabilization and apoptosis sensitization.

    Evidence GST pulldown with MS identification plus cytochrome c release, membrane potential, caspase activation, and PTPC inhibitor assays in purified mitochondria

    PMID:16201016

    Open questions at the time
    • Binding interface on ANT3 not mapped
    • Does not establish whether PB1-F2 acts via ANT3 conformation or VDAC1
    • Endogenous physiological role of ANT3 in pore gating not yet addressed
  3. 2020 High

    Identifying mortalin as an ANT3 chaperone that blocks ANT3-cyclophilin D interaction defined a regulated mechanism keeping the mPTP closed and tied it to MEK-ERK signaling and tumor survival.

    Evidence Proteomics, reciprocal Co-IP, mortalin depletion, MEK-ERK manipulation, and mitochondrial permeability assays in BRAF-mutant cells with in vivo validation

    PMID:32156782

    Open questions at the time
    • Does not define the ANT3 conformational state mortalin enforces
    • CypD binding site on ANT3 unmapped
    • Generality beyond BRAF-mutant context unknown
  4. 2023 Medium

    MRPL12 binding was shown to stabilize the mPTP in renal epithelium, extending the partner-controlled gating model to a physiological injury setting.

    Evidence Co-IP, MRPL12 overexpression, hypoxia/reoxygenation model, mPTP and apoptosis assays in renal tubular epithelial cells

    PMID:37182101

    Open questions at the time
    • Direct binding region on ANT3 not defined
    • Single lab
    • Relationship to mortalin/CypD axis not tested
  5. 2023 Medium

    Zebrafish dosage experiments placed SLC25A6 upstream of KATP channel-dependent cardiac repolarization, revealing an organ-level function beyond apoptosis.

    Evidence In vivo slc25a6 knockdown/overexpression with QTc measurement and pharmacological KATP modulation, plus correlational human cohort data

    PMID:37495650

    Open questions at the time
    • Mechanism linking translocase activity to KATP channel state unknown
    • Human data correlational only
    • Cell type mediating the effect not identified
  6. 2023 Low

    A reported PTPMT1 interaction with SLC25A6 and NDUFS2 hinted at an additional mitochondrial functional axis in pancreatic cancer.

    Evidence Co-IP with PTPMT1 knockdown/inhibition and mitochondrial function assays

    PMID:37034225

    Open questions at the time
    • Single Co-IP without reciprocal validation or mechanistic dissection
    • How the SLC25A6-NDUFS2 axis operates is undefined
    • Functional consequence for ANT3 unknown
  7. 2024 Medium

    EFHD1 was shown to directly inhibit the ANT3 conformational change, and pharmacological rescue with conformation-locking agents established the conformation-to-mPTP-to-chemoresistance causal chain.

    Evidence Co-IP, EFHD1 overexpression/knockdown, mPTP and cisplatin sensitivity assays, and CATR/BKA conformational inhibitor rescue in osteosarcoma cells

    PMID:38795203

    Open questions at the time
    • EFHD1 binding site on ANT3 not mapped
    • Single lab
    • Interplay with other mPTP-restraining partners not tested
  8. 2025 Medium

    MRPL13 was found to drive K48-linked ubiquitination of SLC25A6, defining degradative control of ANT3 abundance that suppresses mPTP opening in ovarian cancer.

    Evidence Co-IP, K48-linkage-specific ubiquitination assay, MRPL13 knockdown/overexpression, mPTP and cytochrome c release assays with in vivo models

    PMID:40841355

    Open questions at the time
    • E3 ligase mediating MRPL13-directed ubiquitination not identified
    • Single lab
    • Relationship to MRPL12 stabilizing role unresolved
  9. 2025 Low

    Carvacrol-driven upregulation of SLC25A6 downstream of VDAC1 inhibition associated ANT3 levels with improved mitochondrial function under inflammatory injury.

    Evidence Western blot, VDAC1 knockdown, mPTP/membrane potential/ROS/ATP assays in LPS-treated endothelial cells

    PMID:40060777

    Open questions at the time
    • SLC25A6-VDAC1 relationship inferred from expression, not direct mechanism
    • No demonstration of physical interaction
    • Single lab
  10. 2026 High

    Discovery that ANT3 binds MIC60 via Thr126 and displaces MIC19 revealed a pore-independent function: destabilizing the MICOS complex to drive mitochondrial fission and apoptosis.

    Evidence Co-IP, T126A site-directed mutagenesis, mitochondrial fragmentation and apoptosis assays, mitofission inhibitors, in vivo cancer models

    PMID:42020360

    Open questions at the time
    • How this function is normally regulated unknown
    • Relationship between MICOS disruption and mPTP gating not integrated
    • Single lab
  11. 2026 High

    SIRT3 was identified as the deacetylase that stabilizes SLC25A6, and XPNPEP2 loss as a route to SIAH1-mediated degradation, establishing reciprocal acetylation- and ubiquitination-dependent control of ANT3 abundance.

    Evidence Co-IP, acetylation and CHX-chase stability assays, SIAH1 ubiquitination assay, epistasis rescue, and in vitro/in vivo cancer and angiogenesis models

    PMID:41573684 PMID:42260555

    Open questions at the time
    • Acetylation site(s) on ANT3 not mapped
    • Integration of deacetylation versus ubiquitination control not resolved
    • Single labs for each axis

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ANT3 conformational state, MICOS disruption, post-translational modification, and nucleotide transport are mechanistically integrated into a unified model of mPTP control remains unresolved.
  • No structural model linking partner binding to conformational state
  • Acetylation and ubiquitination sites unmapped
  • Whether transport activity is required for apoptotic/MICOS functions is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 1 GO:0140104 molecular carrier activity 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-1430728 Metabolism 2
Partners
EFHD1HSPA9MIC60MRPL12MRPL13SIRT3VDAC1XPNPEP2
Complex memberships
mitochondrial permeability transition pore (mPTP/PTPC)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Influenza virus PB1-F2 protein physically interacts with ANT3 (inner mitochondrial membrane) and VDAC1 (outer mitochondrial membrane), as identified by GST pulldown and mass spectrometry. This interaction promotes cytochrome c release, loss of mitochondrial membrane potential, and enhancement of tBid-induced mitochondrial permeabilization, sensitizing cells to apoptosis via the mitochondrial permeability transition pore complex (PTPC). Blockers of PTPC inhibited PB1-F2-induced mitochondrial permeabilization. GST pulldown, mass spectrometry, purified mitochondria assays (cytochrome c release, membrane potential measurement), caspase 3 cleavage assay, PTPC inhibitor experiments PLoS pathogens High 16201016
2005 Human ANT-3 (SLC25A6) expressed in insect cell mitochondria binds the high-affinity inhibitors bongkrekic acid (BKA) and atractyloside (ATR), as well as the natural ligand ADP, with affinities comparable to bovine heart mitochondria, establishing the ligand-binding properties of the human isoform. Ectopic expression of histidine-tagged ANT-3 in Trichoplusia ni cells, radioiodinated ATR binding assay, comparison with bovine heart mitochondria preparations Mitochondrion Medium 16060289
2020 Mortalin (HSPA9) was identified as a chaperone that binds ANT3 (SLC25A6) as a substrate. Mortalin inhibits ANT3 interaction with cyclophilin D (CypD), thereby suppressing mitochondrial permeability transition pore (mPTP) opening. MEK-ERK signaling promotes ANT3-CypD interaction (increasing mitochondrial permeability), while mortalin opposes this. Mortalin depletion in BRAF-mutant cells increases mitochondrial permeability via ANT3-CypD interaction to the point of triggering cell death. Proteomics screening, co-immunoprecipitation, mortalin knockdown/depletion, MEK-ERK pathway manipulation, mitochondrial permeability assays, in vitro and in vivo tumor cell proliferation assays Science signaling High 32156782
2023 MRPL12 specifically binds ANT3 (SLC25A6) under normal physiological conditions, stabilizing the mitochondrial permeability transition pore (MPTP) and maintaining mitochondrial membrane homeostasis in renal tubular epithelial cells. During acute kidney injury, MRPL12 expression decreases, MRPL12-ANT3 interaction is reduced, ANT3 undergoes conformational change, MPTP opens abnormally, and apoptosis ensues. MRPL12 overexpression protected against these effects during hypoxia/reoxygenation. Co-immunoprecipitation, MRPL12 overexpression in renal tubular epithelial cells, hypoxia/reoxygenation model, MPTP opening assay, apoptosis assay iScience Medium 37182101
2023 SLC25A6 dosage inversely correlates with QTc interval duration. Downregulation of slc25a6 in zebrafish increased QTc interval, which was restored by pharmacological inhibition of KATP channels; overexpression of SLC25A6 shortened QTc, normalized by KATP channel activation. This places SLC25A6 upstream of KATP channel activity in cardiac repolarization. In vivo zebrafish slc25a6 knockdown and overexpression, QTc interval measurement, pharmacological KATP channel modulation, human cohort correlation analysis Scientific reports Medium 37495650
2023 PTPMT1 interacts with SLC25A6 (ANT3) and NDUFS2 as shown by co-immunoprecipitation in pancreatic cancer cells, suggesting PTPMT1 modulates mitochondrial function via the SLC25A6-NDUFS2 axis. Co-immunoprecipitation, siRNA knockdown of PTPMT1, pharmacological PTPMT1 inhibition, mitochondrial function assays American journal of cancer research Low 37034225
2024 EFHD1 binds ANT3 (SLC25A6) and inhibits its conformational change, thereby preventing mPTP opening, maintaining mitochondrial function, and promoting osteosarcoma cell survival and chemoresistance. The ANT3 conformational inhibitor carboxyatractyloside (CATR, promoting mPTP opening) enhanced chemosensitivity in EFHD1-overexpressing cells; bongkrekic acid (BKA, inhibiting mPTP opening) restored resistance in EFHD1-knockdown cells. Co-immunoprecipitation, EFHD1 overexpression and knockdown, mPTP opening assay, cisplatin sensitivity assay, pharmacological ANT3 conformational inhibitors (CATR and BKA) Cellular and molecular life sciences : CMLS Medium 38795203
2026 SLC25A6 directly interacts with MIC60 (a core MICOS complex component), competitively inhibiting MIC19 binding to MIC60, thereby destabilizing the MICOS complex and promoting mitochondrial fragmentation (mitofission), dysfunction, and intrinsic apoptosis. The SLC25A6 T126A mutant failed to bind MIC60 and lost its ability to disrupt the MICOS complex or facilitate mitofission. Co-immunoprecipitation, site-directed mutagenesis (T126A), mitochondrial fragmentation assays, apoptosis assays, in vitro and in vivo cancer models, mitofission inhibitor experiments Cell death & disease High 42020360
2026 XPNPEP2 interacts with SLC25A6 in endothelial cells. XPNPEP2 ablation downregulates SLC25A6 via SIAH1-mediated ubiquitin-proteasome degradation, impairing mitochondrial function and angiogenesis. Overexpression of XPNPEP2 restored SLC25A6 levels and EC angiogenic function; silencing SLC25A6 alone recapitulated impaired angiogenesis. Co-immunoprecipitation, XPNPEP2 and SLC25A6 knockdown/overexpression, SIAH1 ubiquitination assay, in vitro and in vivo angiogenesis assays, mitochondrial function assays Frontiers in cell and developmental biology Medium 41573684
2026 SIRT3 directly interacts with SLC25A6 (ANT3) and deacetylates it, reducing its acetylation level and thereby enhancing its protein stability. Stabilized SLC25A6 enhances mitochondrial metabolic activity and promotes gastric cancer progression and cisplatin resistance. SLC25A6 silencing phenocopied SIRT3 knockdown effects, and rescue experiments confirmed that SIRT3's oncogenic and chemoresistant functions are dependent on ANT3. Co-immunoprecipitation, acetylation assays, cycloheximide chase assays, RNA-seq, SIRT3 and SLC25A6 knockdown/overexpression, in vitro and in vivo tumor models, cisplatin resistance assays Journal of translational medicine High 42260555
2025 MRPL13 specifically interacts with SLC25A6 and facilitates its degradation via K48-linked ubiquitination, inhibiting mPTP opening, preventing cytochrome c release into the cytoplasm, inhibiting cell death, and enhancing mitochondrial function in ovarian cancer cells. Co-immunoprecipitation, ubiquitination assay (K48-linkage specificity), MRPL13 knockdown/overexpression, mPTP opening assay, cytochrome c release assay, in vitro and in vivo ovarian cancer models Cell death & disease Medium 40841355
2025 Carvacrol inhibits VDAC1 expression and increases SLC25A6 protein expression in LPS-treated endothelial cells, improving mitochondrial membrane potential, reducing mPTP opening, lowering ROS, and increasing ATP production. VDAC1 knockdown phenocopied carvacrol effects, and SLC25A6 upregulation was identified as acting downstream of VDAC1 inhibition. Western blotting, VDAC1 knockdown, mPTP assay, mitochondrial membrane potential assay, ROS and ATP measurements, LPS-inflammatory injury model ACS omega Low 40060777

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS pathogens 296 16201016
1999 The 3D positioning of ANT2 and ANT3 genes within female X chromosome territories correlates with gene activity. Experimental cell research 101 10527626
1993 A human pseudoautosomal gene encodes the ANT3 ADP/ATP translocase and escapes X-inactivation. Genomics 49 8486369
2006 Characterization of the bifunctional aminoglycoside-modifying enzyme ANT(3'')-Ii/AAC(6')-IId from Serratia marcescens. Biochemistry 48 16819836
2020 Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability. Science signaling 35 32156782
1995 ANT3 and STS are autosomal in prosimian lemurs: implications for the evolution of the pseudoautosomal region. Human genetics 31 7814020
2023 MRPL12-ANT3 interaction involves in acute kidney injury via regulating MPTP of tubular epithelial cells. iScience 17 37182101
2021 Discovery and validation of FBLN1 and ANT3 as potential biomarkers for early detection of cervical cancer. Cancer cell international 14 33602229
2004 Assignment of SRY, ANT3, and CSF2RA to the bovine Y chromosome by FISH and RH mapping. Animal biotechnology 14 15595696
2001 Physical mapping of CSF2RA, ANT3 and STS on the pseudoautosomal region of bovine chromosome X. Animal genetics 11 11421947
2013 Domain dissection and characterization of the aminoglycoside resistance enzyme ANT(3″)-Ii/AAC(6')-IId from Serratia marcescens. Biochimie 10 23485681
2024 EFHD1 promotes osteosarcoma proliferation and drug resistance by inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP) by binding to ANT3. Cellular and molecular life sciences : CMLS 9 38795203
2005 Ectopic expression of the human adenine nucleotide translocase, isoform 3 (ANT-3). Characterization of ligand binding properties. Mitochondrion 8 16060289
2023 Dosage of the pseudoautosomal gene SLC25A6 is implicated in QTc interval duration. Scientific reports 7 37495650
2023 PTPMT1 regulates mitochondrial death through the SLC25A6-NDUFS2 axis in pancreatic cancer cells. American journal of cancer research 6 37034225
2021 Identification and Characterization of a Novel Aminoglycoside 3''-Nucleotidyltransferase, ANT(3'')-IId, From Acinetobacter lwoffii. Frontiers in microbiology 6 34531844
2009 Isolation, nucleotide identification and tissue expression of three novel ovine genes-SLC25A4, SLC25A5 and SLC25A6. Molecular biology reports 5 19763879
2025 Carvacrol Regulates the Expression of SLC25A6 by Inhibiting VDAC1 to Improve Mitochondrial Function and Reduce LPS-Induced Inflammatory Injury in HMEC-1 Cells. ACS omega 3 40060777
2025 MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6. Cell death & disease 2 40841355
2025 Identification of a novel aminoglycoside nucleotidyltransferase ANT(3″)-Ic from Citrobacter telavivum S24. BMC microbiology 1 40847386
2026 XPNPEP2 regulates angiogenesis via modulation of mitochondrial function through SLC25A6. Frontiers in cell and developmental biology 0 41573684
2026 Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer. Cell death & disease 0 42020360
2026 SIRT3 regulates mitochondrial metabolism through deacetylation of SLC25A6 to impact gastric cancer progression and drug resistance. Journal of translational medicine 0 42260555

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