Affinage

SLC25A6

ADP/ATP translocase 3 · UniProt P12236

Round 2 corrected
Length
298 aa
Mass
32.9 kDa
Annotated
2026-04-28
52 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC25A6 (ANT3) is an inner mitochondrial membrane ADP/ATP antiporter that exchanges cytosolic ADP for matrix ATP and serves as a critical regulator of mitochondrial permeability transition pore (mPTP) opening and mitochondrial integrity. Its transport function has been confirmed by reconstitution into liposomes with canonical ANT ligand binding (atractyloside, bongkrekic acid, ADP) (PMID:23266187, PMID:16060289), while its conformational state governs mPTP gating: interaction partners including MRPL12, mortalin/HSPA9, and EFHD1 stabilize ANT3 to prevent mPTP opening, whereas loss of these interactions or MEK-ERK signaling promotes the cyclophilin D–ANT3 complex and lethal permeabilization (PMID:32156782, PMID:37182101, PMID:38795203). Beyond mPTP regulation, SLC25A6 directly binds the MICOS component MIC60 under metabolic stress, competitively displacing MIC19 to destabilize cristae architecture and trigger mitochondrial fragmentation and apoptosis (PMID:42020360). SLC25A6 dosage modulates cardiac QTc interval duration upstream of mitochondrial KATP channels, as demonstrated by zebrafish knockdown/overexpression and human sex-chromosome aneuploid cohorts (PMID:37495650).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1993 High

    Establishing the genomic identity and escape from X-inactivation resolved why ANT3 is expressed from both sex chromosomes and varies with sex-chromosome dosage.

    Evidence Genomic cloning, FISH mapping to PAR at Xp22.3, and transcription analysis from active/inactive X and Y chromosomes

    PMID:8486369

    Open questions at the time
    • Functional consequences of dosage variation were not explored
    • No protein-level expression quantification across tissues
  2. 2005 High

    Demonstrating that SLC25A6 binds canonical ANT ligands with expected affinities and that it interacts with VDAC1 and the influenza PB1-F2 protein to mediate cytochrome c release established ANT3 as both a bona fide ADP/ATP translocase and a component of the permeability transition pore complex exploited by pathogens.

    Evidence Heterologous expression with radioligand binding (ATR, BKA, ADP); GST pulldown/MS identification of PB1-F2–ANT3–VDAC1 interaction; cytochrome c release and membrane potential assays on purified mitochondria

    PMID:16060289 PMID:16201016

    Open questions at the time
    • Transport kinetics of recombinant human ANT3 not measured in liposomes at this stage
    • Structural basis of PB1-F2 interaction unknown
  3. 2012 High

    Systematic reconstitution of SLC25 family members into liposomes confirmed SLC25A6 as an ADP/ATP antiporter with the conserved tripartite six-transmembrane architecture, anchoring its classification within the carrier superfamily.

    Evidence Heterologous expression, purification, and transport assay in liposomes as part of SLC25 family characterization

    PMID:23266187

    Open questions at the time
    • No isoform-specific kinetic comparison among ANT1-4 under identical conditions
    • Post-translational regulation of transport activity not addressed
  4. 2020 High

    Identifying mortalin/HSPA9 as a chaperone that suppresses the ANT3–cyclophilin D interaction revealed the first mechanism by which oncogenic MEK-ERK signaling controls mPTP opening through ANT3, linking mitochondrial permeability to cancer cell survival.

    Evidence Reciprocal co-IP of mortalin–ANT3 and ANT3–CypD; mortalin depletion causing lethal mitochondrial permeabilization in BRAF-V600E cells; in vivo tumor models

    PMID:32156782

    Open questions at the time
    • Direct phosphorylation site on ANT3 downstream of MEK-ERK not identified
    • Structural basis of mortalin–ANT3 interaction unresolved
  5. 2023 High

    Discovery that MRPL12 binds and stabilizes ANT3 to prevent mPTP opening during renal injury, and that SLC25A6 dosage modulates cardiac QTc interval via mitochondrial KATP channels, broadened the physiological scope of ANT3 regulation beyond cancer.

    Evidence Co-IP of MRPL12–ANT3, gain/loss-of-function with mPTP and apoptosis readouts in renal epithelial cells and AKI mouse model; zebrafish slc25a6 knockdown/overexpression with ECG and KATP pharmacological epistasis; human TS/KS cohort analysis

    PMID:37182101 PMID:37495650

    Open questions at the time
    • MRPL12 binding site on ANT3 not mapped
    • Mechanism coupling ANT3 transport to KATP channel activity is unknown
    • QTc findings rely on zebrafish and human association—mammalian cardiac-specific models lacking
  6. 2024 High

    Showing that EFHD1 inhibits ANT3 conformational change to block mPTP opening—reversible by the ANT3 ligands CATR and BKA—provided pharmacological epistasis evidence that ANT3 conformation is the direct regulatory node for mPTP gating and chemoresistance.

    Evidence Co-IP; EFHD1 overexpression/knockdown with mPTP assays; pharmacological reversal with CATR and BKA in osteosarcoma cells

    PMID:38795203

    Open questions at the time
    • EFHD1 binding domain on ANT3 not mapped
    • Whether EFHD1 regulation occurs in non-cancer tissues is untested
  7. 2025 High

    Identification of MRPL13-mediated K48-ubiquitination and XPNPEP2/SIAH1-mediated degradation of SLC25A6 established two distinct protein-level regulatory circuits controlling ANT3 abundance and, consequently, mPTP opening and mitochondrial function.

    Evidence Reciprocal co-IP; K48-ubiquitin linkage assay for MRPL13–SLC25A6; XPNPEP2 KO with SIAH1 ubiquitination assay; mitochondrial function, angiogenesis, and xenograft models

    PMID:40841355 PMID:41573684

    Open questions at the time
    • Ubiquitination sites on SLC25A6 not identified
    • Whether MRPL13 and SIAH1 pathways are redundant or tissue-specific is unknown
    • E3 ligase for MRPL13-promoted ubiquitination not named
  8. 2026 High

    Demonstrating that SLC25A6 directly binds MIC60 via T126, competitively displacing MIC19 to disrupt MICOS and trigger mitofission, revealed a non-transport, structural role for ANT3 in cristae remodeling under metabolic stress.

    Evidence Co-IP; T126A mutagenesis abolishing MIC60 binding and mitofission; single-cell caspase-3 monitoring; mitofission inhibitor epistasis; in vivo xenograft

    PMID:42020360

    Open questions at the time
    • Structural basis of T126-dependent MIC60 binding is unresolved
    • Whether MICOS disruption is separable from mPTP regulation is not clear
    • Physiological triggers beyond glutamine deprivation not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the high-resolution structure of human ANT3 in complex with its regulatory partners (CypD, mortalin, MIC60), the identity of ubiquitination sites controlling its turnover, and whether its MICOS-disrupting and mPTP-gating functions are independently regulated or mechanistically coupled.
  • No cryo-EM or crystal structure of human ANT3 with any binding partner
  • Ubiquitination sites on SLC25A6 unmapped
  • Relationship between MICOS disruption and mPTP opening not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0140104 molecular carrier activity 2
Localization
GO:0005739 mitochondrion 8
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-1430728 Metabolism 2 R-HSA-382551 Transport of small molecules 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
EFHD1HSPA9MIC60MRPL12MRPL13PPIFVDAC1XPNPEP2
Complex memberships
Permeability transition pore complex (mPTP/PTPC)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The human ANT3 gene (SLC25A6) is located in the pseudoautosomal region (PAR) proximal to CSF2RA on Xp22.3, is transcribed from both active and inactive X chromosomes and from the Y chromosome, and therefore escapes X-inactivation. A likely pseudogene maps to chromosome 9. Genomic cloning, Southern blotting, FISH, transcription analysis of X-inactivation Genomics High 8486369
2005 Influenza virus PB1-F2 protein physically interacts with the inner mitochondrial membrane adenine nucleotide translocator ANT3 (SLC25A6) and the outer membrane VDAC1, and this interaction mediates cytochrome c release, loss of mitochondrial membrane potential, enhancement of tBid-induced permeabilization, and sensitization of cells to apoptosis. Blockers of the permeability transition pore complex (PTPC) inhibit PB1-F2-induced mitochondrial permeabilization. GST pulldown with subsequent mass spectrometric identification; recombinant protein treatment of purified mouse liver mitochondria; cytochrome c release assay; mitochondrial membrane potential measurement; caspase-3 cleavage assay PLoS pathogens High 16201016
2005 Human ANT-3 (SLC25A6) was cloned from heart cDNA, expressed as a His-tagged fusion in insect cell mitochondria, and shown to bind the canonical ANT ligands bongkrekic acid (BKA), atractyloside (ATR), and ADP with affinities similar to those measured in bovine heart mitochondria, confirming that SLC25A6 is a functional ADP/ATP translocase. Heterologous expression in Trichoplusia ni cells; radioiodinated ATR binding assay; BKA and ADP competition binding Mitochondrion Medium 16060289
2007 SIRT4, a mitochondrial ADP-ribosyltransferase, co-immunoprecipitates with ANT3 (SLC25A6) and ANT2, identifying SLC25A6 as a mitochondrial matrix interaction partner of SIRT4 involved in regulation of insulin secretion. Mass spectrometry analysis of SIRT4 co-immunoprecipitates; mitochondrial localization by fractionation The Journal of biological chemistry Medium 17715127
2012 SLC25A6 (ANT3) is a member of the SLC25 inner mitochondrial membrane transporter superfamily characterised by a tripartite structure, six transmembrane α-helices, and a 3-fold repeated signature motif; it functions as an ADP/ATP antiporter whose substrate specificity and transport mode have been confirmed by reconstitution into liposomes. Reconstitution into liposomes; transport assays after heterologous expression and purification (as part of systematic SLC25 family characterization) Molecular aspects of medicine High 23266187
2020 Mortalin (HSPA9/GRP75) directly suppresses ANT3 (SLC25A6)-mediated mitochondrial membrane permeabilization by inhibiting the ANT3–cyclophilin D (CypD) interaction. Elevated MEK-ERK signaling promotes ANT3–CypD interaction and increases mitochondrial permeability, while mortalin opposes this, maintaining cell survival. Loss of mortalin in BRAF-V600E cells causes lethal mitochondrial permeabilization through ANT3. Proteomics screening identifying ANT3 as mortalin substrate; co-immunoprecipitation of ANT3–CypD and mortalin–ANT3 complexes; mortalin depletion/overexpression with mitochondrial permeability and cell viability readouts; in vivo tumor models Science signaling High 32156782
2023 MRPL12 (mitochondrial ribosomal protein L7/L12) specifically binds ANT3 (SLC25A6) under 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, the MRPL12–ANT3 interaction is reduced, causing ANT3 conformational change, aberrant mPTP opening, and apoptosis. MRPL12 overexpression protects cells from mPTP opening during hypoxia/reoxygenation. Co-immunoprecipitation; gain- and loss-of-function (overexpression/knockdown); mPTP opening assay; mitochondrial membrane potential measurement; apoptosis assay; in vivo AKI mouse model iScience High 37182101
2023 SLC25A6 dosage negatively correlates with QTc interval duration: lower SLC25A6 expression (as in Turner syndrome) is associated with prolonged QTc, while higher expression (as in Klinefelter syndrome) associates with shortened QTc. In zebrafish, slc25a6 knockdown increased QTc interval duration (rescued by KATP channel inhibition), and overexpression shortened QTc (rescued by KATP channel activation), placing SLC25A6 upstream of mitochondrial KATP channel activity in cardiac repolarization. Human clinical cohort analysis (TS and KS patients, gene expression vs QTc); zebrafish slc25a6 knockdown and overexpression with ECG QTc measurement; pharmacological KATP channel modulation Scientific reports Medium 37495650
2023 PTPMT1 (a mitochondrial dual-specificity phosphatase) co-immunoprecipitates with SLC25A6 and NDUFS2, suggesting it modulates mitochondrial function via a SLC25A6–NDUFS2 axis; PTPMT1 silencing reduces cell viability and impairs mitochondrial function in pancreatic cancer cells. Co-immunoprecipitation; siRNA knockdown and pharmacological 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 and maintaining mitochondrial function. This interaction promotes osteosarcoma chemoresistance. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which promotes mPTP opening, overcomes EFHD1-mediated resistance, while bongkrekic acid (BKA), which inhibits mPTP opening, restores resistance in EFHD1-knockdown cells. Co-immunoprecipitation; EFHD1 overexpression/knockdown with mPTP opening assay and drug sensitivity readouts; pharmacological ANT3 conformational inhibitors (CATR and BKA) Cellular and molecular life sciences : CMLS High 38795203
2025 MRPL13 (mitochondrial ribosomal protein L13) physically interacts with SLC25A6 and promotes its degradation via K48-linked ubiquitination. By accelerating SLC25A6 degradation, MRPL13 inhibits mPTP opening and prevents cytochrome c release, thereby enhancing mitochondrial function and promoting ovarian cancer cell survival. Knockdown of MRPL13 impairs OXPHOS, increases ROS, causes mitochondrial depolarization and mPTP opening. Co-immunoprecipitation; ubiquitination assay (K48 linkage-specific); MRPL13 knockdown/overexpression; mPTP opening, ROS, OXPHOS, and cytochrome c release assays; in vivo xenograft models Cell death & disease High 40841355
2025 Carvacrol reduces VDAC1 expression and increases SLC25A6 protein expression in LPS-injured endothelial cells, improving mitochondrial membrane potential, reducing mPTP opening and ROS, and increasing ATP production. VDAC1 knockdown phenocopies carvacrol, placing SLC25A6 as a downstream effector of VDAC1 in regulating mitochondrial function during inflammatory injury. Western blot; VDAC1 siRNA knockdown; mPTP opening assay; mitochondrial membrane potential, ROS, and ATP measurement; apoptosis assay ACS omega Low 40060777
2025 XPNPEP2 physically interacts with SLC25A6 in endothelial cells, and XPNPEP2 ablation reduces SLC25A6 protein levels via SIAH1 E3 ligase-mediated ubiquitin degradation. Loss of SLC25A6 impairs mitochondria-associated membranes and mitochondrial function (ATP, mROS, respiration chain), reducing endothelial angiogenesis. Overexpression of XPNPEP2 restores SLC25A6 levels and rescues angiogenic defects. Co-immunoprecipitation; XPNPEP2 knockout in vivo and in vitro; SLC25A6 silencing; SIAH1 ubiquitination assay; mitochondrial function assays; angiogenesis (tube formation, migration) assays Frontiers in cell and developmental biology Medium 41573684
2026 Under glutamine metabolic stress, SLC25A6 is upregulated and directly interacts with MIC60 (a core MICOS complex component), competitively inhibiting MIC19 binding to MIC60 and destabilizing the mitochondrial contact site and cristae organizing system (MICOS). This leads to mitochondrial fragmentation (mitofission) and intrinsic apoptosis. A SLC25A6 T126A mutant fails to bind MIC60 and loses the ability to disrupt MICOS and promote mitofission, establishing T126 as critical for MIC60 binding. Co-immunoprecipitation; site-directed mutagenesis (T126A); mitofission markers; caspase-3 activity indicator (single-cell monitoring); mitofission inhibitor epistasis; in vivo xenograft models Cell death & disease High 42020360

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2012 The mitochondrial transporter family SLC25: identification, properties and physiopathology. Molecular aspects of medicine 492 23266187
2000 Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science (New York, N.Y.) 481 10926541
2020 SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses. Cell 449 33080218
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2000 The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. The Journal of experimental medicine 392 10620603
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2007 Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. The Journal of biological chemistry 332 17715127
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2005 Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS pathogens 293 16201016
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2022 Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 256 35063084
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2018 K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains. Proceedings of the National Academy of Sciences of the United States of America 227 29378950
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 48 8486369
2006 Characterization of the bifunctional aminoglycoside-modifying enzyme ANT(3'')-Ii/AAC(6')-IId from Serratia marcescens. Biochemistry 46 16819836
2020 Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability. Science signaling 34 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 8 38795203
2005 Ectopic expression of the human adenine nucleotide translocase, isoform 3 (ANT-3). Characterization of ligand binding properties. Mitochondrion 8 16060289
2023 PTPMT1 regulates mitochondrial death through the SLC25A6-NDUFS2 axis in pancreatic cancer cells. American journal of cancer research 6 37034225
2023 Dosage of the pseudoautosomal gene SLC25A6 is implicated in QTc interval duration. Scientific reports 6 37495650
2021 Identification and Characterization of a Novel Aminoglycoside 3''-Nucleotidyltransferase, ANT(3'')-IId, From Acinetobacter lwoffii. Frontiers in microbiology 5 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 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
2025 MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6. Cell death & disease 0 40841355