{"gene":"SLC25A6","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1993,"finding":"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.","method":"Genomic cloning, Southern blotting, FISH, transcription analysis of X-inactivation","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — direct genomic mapping and transcriptional analysis, replicated by subsequent studies across species","pmids":["8486369"],"is_preprint":false},{"year":2005,"finding":"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.","method":"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","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pulldown/MS, functional mitochondrial assays, cellular apoptosis readouts) in a single rigorous study","pmids":["16201016"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Heterologous expression in Trichoplusia ni cells; radioiodinated ATR binding assay; BKA and ADP competition binding","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro ligand binding with functional reconstitution, single lab","pmids":["16060289"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Mass spectrometry analysis of SIRT4 co-immunoprecipitates; mitochondrial localization by fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP/MS identification without further mechanistic dissection of the SLC25A6 interaction","pmids":["17715127"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Reconstitution into liposomes; transport assays after heterologous expression and purification (as part of systematic SLC25 family characterization)","journal":"Molecular aspects of medicine","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in liposomes with transport assay, part of systematic family characterization reviewed across multiple studies","pmids":["23266187"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, proteomics, loss-of-function with defined mitochondrial permeability phenotype, in vivo validation","pmids":["32156782"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; gain- and loss-of-function (overexpression/knockdown); mPTP opening assay; mitochondrial membrane potential measurement; apoptosis assay; in vivo AKI mouse model","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, multiple orthogonal functional assays, in vivo validation","pmids":["37182101"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo zebrafish model with pharmacological epistasis, supported by human cohort data","pmids":["37495650"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; siRNA knockdown and pharmacological inhibition; mitochondrial function assays","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP without mechanistic dissection of SLC25A6's specific role in the complex","pmids":["37034225"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation; EFHD1 overexpression/knockdown with mPTP opening assay and drug sensitivity readouts; pharmacological ANT3 conformational inhibitors (CATR and BKA)","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 — co-IP, pharmacological epistasis with specific ANT3 ligands, gain/loss-of-function with defined mPTP and chemoresistance phenotypes","pmids":["38795203"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assay (K48 linkage-specific); MRPL13 knockdown/overexpression; mPTP opening, ROS, OXPHOS, and cytochrome c release assays; in vivo xenograft models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, mechanistic ubiquitination assay, multiple orthogonal mitochondrial phenotypic readouts, in vivo validation","pmids":["40841355"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Western blot; VDAC1 siRNA knockdown; mPTP opening assay; mitochondrial membrane potential, ROS, and ATP measurement; apoptosis assay","journal":"ACS omega","confidence":"Low","confidence_rationale":"Tier 3 — indirect regulatory relationship inferred from knockdown and drug treatment without direct binding evidence between VDAC1 and SLC25A6","pmids":["40060777"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation; XPNPEP2 knockout in vivo and in vitro; SLC25A6 silencing; SIAH1 ubiquitination assay; mitochondrial function assays; angiogenesis (tube formation, migration) assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP, ubiquitination mechanism identified, loss-of-function with defined angiogenic phenotype; single lab","pmids":["41573684"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation; site-directed mutagenesis (T126A); mitofission markers; caspase-3 activity indicator (single-cell monitoring); mitofission inhibitor epistasis; in vivo xenograft models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — co-IP, mutagenesis defining binding residue, pharmacological epistasis, in vivo validation; multiple orthogonal methods","pmids":["42020360"],"is_preprint":false}],"current_model":"SLC25A6 (ANT3) is an inner mitochondrial membrane ADP/ATP antiporter located in the pseudoautosomal region that escapes X-inactivation; it regulates mitochondrial membrane permeability transition pore (mPTP) opening through conformational states controlled by interacting partners including MRPL12 (stabilizing), mortalin/HSPA9 (inhibiting ANT3–CypD interaction), EFHD1 (inhibiting conformational change), and MRPL13 (promoting K48-ubiquitin-dependent SLC25A6 degradation); additionally, SLC25A6 directly binds MIC60 to disrupt the MICOS complex and promote mitofission under metabolic stress, is targeted by viral proteins (influenza PB1-F2) to induce apoptosis, modulates cardiac repolarization (QTc interval) upstream of mitochondrial KATP channels, and is regulated at the protein level by XPNPEP2 via SIAH1-mediated ubiquitination."},"narrative":{"teleology":[{"year":1993,"claim":"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","pmids":["8486369"],"confidence":"High","gaps":["Functional consequences of dosage variation were not explored","No protein-level expression quantification across tissues"]},{"year":2005,"claim":"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","pmids":["16060289","16201016"],"confidence":"High","gaps":["Transport kinetics of recombinant human ANT3 not measured in liposomes at this stage","Structural basis of PB1-F2 interaction unknown"]},{"year":2012,"claim":"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","pmids":["23266187"],"confidence":"High","gaps":["No isoform-specific kinetic comparison among ANT1-4 under identical conditions","Post-translational regulation of transport activity not addressed"]},{"year":2020,"claim":"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","pmids":["32156782"],"confidence":"High","gaps":["Direct phosphorylation site on ANT3 downstream of MEK-ERK not identified","Structural basis of mortalin–ANT3 interaction unresolved"]},{"year":2023,"claim":"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","pmids":["37182101","37495650"],"confidence":"High","gaps":["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"]},{"year":2024,"claim":"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","pmids":["38795203"],"confidence":"High","gaps":["EFHD1 binding domain on ANT3 not mapped","Whether EFHD1 regulation occurs in non-cancer tissues is untested"]},{"year":2025,"claim":"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","pmids":["40841355","41573684"],"confidence":"High","gaps":["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"]},{"year":2026,"claim":"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","pmids":["42020360"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,2,4,5,6,9,10,13]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,5,6,9,10,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[13]}],"complexes":["Permeability transition pore complex (mPTP/PTPC)"],"partners":["HSPA9","PPIF","MRPL12","EFHD1","MRPL13","MIC60","VDAC1","XPNPEP2"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P12236","full_name":"ADP/ATP translocase 3","aliases":["ADP,ATP carrier protein 3","ADP,ATP carrier protein, isoform T2","ANT 2","Adenine nucleotide translocator 3","ANT 3","Solute carrier family 25 member 6"],"length_aa":298,"mass_kda":32.9,"function":"ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (By similarity). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity). In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (PubMed:15033708). Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A6/ANT3 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity) (By similarity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it (By similarity). Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death (PubMed:15033708). It is however unclear if SLC25A6/ANT3 constitutes a pore-forming component of mPTP or regulates it (By similarity)","subcellular_location":"Mitochondrion inner membrane; Membrane","url":"https://www.uniprot.org/uniprotkb/P12236/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC25A6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ASS1","stoichiometry":0.2},{"gene":"PHGDH","stoichiometry":0.2},{"gene":"SARS","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SLC25A6","total_profiled":1310},"omim":[{"mim_id":"618566","title":"ADENINE NUCLEOTIDE TRANSLOCASE LYSINE METHYLTRANSFERASE; ANTKMT","url":"https://www.omim.org/entry/618566"},{"mim_id":"610826","title":"SOLUTE CARRIER FAMILY 25, MEMBER 46; SLC25A46","url":"https://www.omim.org/entry/610826"},{"mim_id":"609260","title":"CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2A2A; CMT2A2A","url":"https://www.omim.org/entry/609260"},{"mim_id":"608507","title":"MITOFUSIN 2; MFN2","url":"https://www.omim.org/entry/608507"},{"mim_id":"403000","title":"SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, ADENINE NUCLEOTIDE TRANSLOCATOR), MEMBER A6, Y-CHROMOSOMAL; SLC25A6","url":"https://www.omim.org/entry/403000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC25A6"},"hgnc":{"alias_symbol":["ANT3Y","MGC17525"],"prev_symbol":["ANT3"]},"alphafold":{"accession":"P12236","domains":[{"cath_id":"1.50.40.10","chopping":"2-294","consensus_level":"medium","plddt":92.1013,"start":2,"end":294}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12236","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12236-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12236-F1-predicted_aligned_error_v6.png","plddt_mean":92.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC25A6","jax_strain_url":"https://www.jax.org/strain/search?query=SLC25A6"},"sequence":{"accession":"P12236","fasta_url":"https://rest.uniprot.org/uniprotkb/P12236.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12236/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12236"}},"corpus_meta":[{"pmid":"16201016","id":"PMC_16201016","title":"Influenza 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identified by GST pulldown and mass spectrometry; this interaction promotes mitochondrial permeability transition, cytochrome c release, and loss of mitochondrial membrane potential, sensitizing cells to apoptosis.\",\n      \"method\": \"GST pulldown with mass spectrometry, recombinant protein treatment of isolated mitochondria, cytochrome c release assay, mitochondrial membrane potential measurement\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown + MS identification + functional reconstitution in isolated mitochondria, multiple orthogonal readouts\",\n      \"pmids\": [\"16201016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human ANT-3 (SLC25A6) expressed in insect cell mitochondria binds the high-affinity inhibitors bongkrekic acid (BKA) and atractyloside (ATR) as well as ADP with affinities similar to those of bovine heart mitochondrial ANT, confirming functional conservation of ligand-binding properties of this isoform.\",\n      \"method\": \"Ectopic expression in Trichoplusia ni cells, radioiodinated ATR binding assay, BKA and ADP competition binding\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 in vitro binding assay — single lab, single method set but direct biochemical characterization\",\n      \"pmids\": [\"16060289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANT3 (SLC25A6) is a substrate of the mitochondrial chaperone mortalin (HSPA9); mortalin binding to ANT3 inhibits ANT3–cyclophilin D (CypD) interaction, thereby decreasing mitochondrial permeability. MEK-ERK signaling promotes ANT3–CypD interaction and increases mitochondrial permeability, while mortalin opposes this effect.\",\n      \"method\": \"Proteomics screening, co-immunoprecipitation, mortalin depletion/overexpression with mitochondrial permeability readouts, cell viability assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, proteomics identification, multiple orthogonal functional readouts, in vivo tumor model\",\n      \"pmids\": [\"32156782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MRPL12 specifically binds ANT3 (SLC25A6) under normal physiological conditions in renal tubular epithelial cells, stabilizing the mitochondrial permeability transition pore (MPTP) and maintaining mitochondrial membrane homeostasis; decreased MRPL12 during acute kidney injury reduces this interaction, leading to ANT3 conformational change, aberrant MPTP opening, and cell apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, MRPL12 overexpression/knockdown, MPTP opening assay, hypoxia/reoxygenation model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus loss/gain of function with defined mitochondrial phenotype, single lab\",\n      \"pmids\": [\"37182101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTPMT1 physically interacts with SLC25A6 and NDUFS2 in pancreatic cancer cells, as shown by co-immunoprecipitation, suggesting SLC25A6 functions within a PTPMT1-SLC25A6-NDUFS2 axis to modulate mitochondrial function.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with mitochondrial function readouts\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP, limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"37034225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC25A6 gene dosage inversely correlates with QTc interval duration; downregulation of slc25a6 in zebrafish prolongs QTc, which is rescued by pharmacological inhibition of KATP channels, while overexpression shortens QTc, reversed by KATP channel activation, placing SLC25A6 upstream of KATP channel activity in cardiac repolarization.\",\n      \"method\": \"In vivo zebrafish knockdown/overexpression, pharmacological rescue with KATP channel modulators, QTc measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic manipulation with pharmacological epistasis rescue, replicated in human and zebrafish models\",\n      \"pmids\": [\"37495650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EFHD1 binds directly to ANT3 (SLC25A6) and inhibits its conformational change, thereby suppressing mPTP opening and maintaining mitochondrial function; pharmacological conformational inhibitors of ANT3 (CATR or BKA) phenocopy or reverse EFHD1 effects on mPTP, confirming that EFHD1 acts through ANT3 conformation to regulate cell survival.\",\n      \"method\": \"Co-immunoprecipitation, EFHD1 overexpression/knockdown, mPTP opening assay, pharmacological ANT3 inhibitors (CATR, BKA), cisplatin resistance assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus pharmacological epistasis with conformational ANT3 inhibitors, single lab\",\n      \"pmids\": [\"38795203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MRPL13 interacts with SLC25A6, facilitating its degradation via K48-linked ubiquitination; this reduces mPTP opening, prevents cytochrome c release, and enhances mitochondrial function in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage), MRPL13 knockdown/overexpression, cytochrome c release, mPTP assay, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination assay plus in vivo functional validation, single lab\",\n      \"pmids\": [\"40841355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SLC25A6 directly interacts with MIC60 (a MICOS complex component), competitively inhibiting MIC19 binding; the T126A mutant of SLC25A6 fails to bind MIC60 and cannot destabilize the MICOS complex or promote mitochondrial fission, placing SLC25A6-mediated MICOS disruption upstream of mitofission and intrinsic apoptosis under glutamine metabolic stress.\",\n      \"method\": \"Co-immunoprecipitation, SLC25A6 overexpression/knockdown, site-directed mutagenesis (T126A), mitochondrial fission markers, caspase-3 activity indicator, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus mutagenesis demonstrating loss of interaction and function, in vitro and in vivo, single lab\",\n      \"pmids\": [\"42020360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"XPNPEP2 interacts with SLC25A6; XPNPEP2 ablation reduces SLC25A6 protein levels via SIAH1-mediated ubiquitin-dependent degradation, impairing mitochondrial function and angiogenesis in endothelial cells; SLC25A6 silencing alone recapitulates the angiogenic defects.\",\n      \"method\": \"Co-immunoprecipitation, XPNPEP2 knockout/overexpression, SIAH1 ubiquitination pathway, SLC25A6 siRNA knockdown, in vitro tube formation and migration, in vivo vascular phenotype\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus epistasis rescue plus ubiquitination mechanism, multiple readouts, single lab\",\n      \"pmids\": [\"41573684\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A6 (ANT3) is an inner mitochondrial membrane ADP/ATP translocase that functions as a key regulator of the mitochondrial permeability transition pore (mPTP): its conformational state—modulated by binding partners including mortalin/HSPA9, MRPL12, MRPL13, EFHD1, and viral PB1-F2—controls mPTP opening, cytochrome c release, and apoptosis; additionally, SLC25A6 interacts with the MICOS component MIC60 to regulate mitochondrial fission, is subject to ubiquitin-mediated degradation (via SIAH1 and MRPL13), and acts upstream of KATP channels to influence cardiac repolarization.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:16201016 — influenza PB1-F2 interacts with ANT3 (SLC25A6) → KEEP\n2. PMID:10527626 — 3D positioning of ANT2/ANT3 genes, X chromosome territory → KEEP (genomic/localization context for SLC25A6)\n3. PMID:8486369 — ANT3 pseudoautosomal gene, escapes X-inactivation → KEEP\n4. PMID:16819836 — ANT(3'')-Ii/AAC(6')-IId from Serratia marcescens — bacterial aminoglycoside enzyme, SYMBOL COLLISION → EXCLUDE\n5. PMID:32156782 — mortalin suppresses ANT3-mediated mitochondrial permeability → KEEP\n6. PMID:7814020 — ANT3 autosomal in prosimian lemurs, evolution of PAR → KEEP (genomic)\n7. PMID:37182101 — MRPL12-ANT3 interaction, MPTP regulation in AKI → KEEP\n8. PMID:33602229 — ANT3 as cervical cancer biomarker, expression correlation → mostly expression, but includes CRISPR loss-of-function linking HPV E6/E7 to ANT3 expression → weak mechanistic link, borderline; no direct mechanism of protein function → EXCLUDE\n9. PMID:15595696 — bovine FISH/RH mapping of ANT3 → genomic mapping only, no mechanism → EXCLUDE\n10. PMID:11421947 — bovine chromosome X PAR mapping → genomic mapping only → EXCLUDE\n11. PMID:23485681 — domain dissection of bacterial ANT(3'')-Ii/AAC(6')-IId — SYMBOL COLLISION → EXCLUDE\n12. PMID:38795203 — EFHD1 binds ANT3, inhibits mPTP opening → KEEP\n13. PMID:16060289 — ectopic expression of human ANT-3, ligand binding characterization → KEEP\n14. PMID:37495650 — SLC25A6 dosage and QTc interval, zebrafish functional model → KEEP\n15. PMID:37034225 — PTPMT1 interacts with SLC25A6 and NDUFS2, mitochondrial function → KEEP\n16. PMID:19763879 — ovine SLC25A6 cloning, tissue expression → mostly expression, no direct mechanism → EXCLUDE\n17. PMID:34531844 — ANT(3'')-IId from Acinetobacter — bacterial enzyme, SYMBOL COLLISION → EXCLUDE\n18. PMID:40060777 — carvacrol regulates SLC25A6 via VDAC1, mitochondrial function → KEEP\n19. PMID:40847386 — ANT(3'')-Ic from Citrobacter — bacterial enzyme, SYMBOL COLLISION → EXCLUDE\n20. PMID:40841355 — MRPL13 interacts with SLC25A6, K48-ubiquitination degradation, mPTP → KEEP\n21. PMID:42020360 — SLC25A6 interacts with MIC60, disrupts MICOS, promotes mitofission → KEEP\n22. PMID:41573684 — XPNPEP2 interacts with SLC25A6, SIAH1-mediated degradation, angiogenesis → KEEP\n\nGene2pubmed papers:\n- PMID:16189514, 16169070, 12477932, 26186194, 28514442, 26496610, 25416956 — interactome/cDNA databases, no specific SLC25A6 mechanism → EXCLUDE\n- PMID:29507755 — m6A methylation, no SLC25A6 → EXCLUDE\n- PMID:14702039 — cDNA sequences → EXCLUDE\n- PMID:33961781 — BioPlex 3.0, large-scale interactome → EXCLUDE\n- PMID:22939629 — protein complexes census → EXCLUDE\n- PMID:21873635 — GO propagation → EXCLUDE\n- PMID:29395067 — mRNA granules BioID → EXCLUDE\n- PMID:28302793 — splicing/indisulam → EXCLUDE\n- PMID:23266187 — SLC25 family review → KEEP (mechanistic context for SLC25A6 as ADP/ATP transporter)\n- PMID:10926541 — ANT1 mtDNA maintenance; about ANT1 (SLC25A4), not SLC25A6 → EXCLUDE\n- PMID:33080218 — SARS-CoV-2, no SLC25A6 → EXCLUDE\n- PMID:15489334 — MGC cDNA resource → EXCLUDE\n- PMID:35271311 — OpenCell, large-scale localization → EXCLUDE\n- PMID:26344197 — metazoan complexes → EXCLUDE\n- PMID:10620603 — HIV Vpr apoptosis via ANT/VDAC; mentions ANT broadly, implicates the translocator family in PTPC → marginal; describes ANT generally not specifically SLC25A6 → EXCLUDE\n- PMID:17715127 — SIRT4 ADP-ribosyltransferase, coimmunoprecipitates with ANT2 and ANT3 → KEEP\n- PMID:21145461 — CRL ubiquitin ligase, no SLC25A6 → EXCLUDE\n- PMID:27342126 — Zika/dengue genomics → EXCLUDE\n- PMID:26949251 — Ki-67 heterochromatin → EXCLUDE\n- PMID:35063084 — Tau interactome → EXCLUDE\n- PMID:34800366 — mitochondrial proteome, defines SLC25A6 as mitochondrial protein → EXCLUDE (no specific mechanistic finding)\n- PMID:29378950 — K63 ubiquitin → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"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.\",\n      \"method\": \"Genomic cloning, Southern blotting, FISH, transcription analysis of X-inactivation\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic mapping and transcriptional analysis, replicated by subsequent studies across species\",\n      \"pmids\": [\"8486369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pulldown/MS, functional mitochondrial assays, cellular apoptosis readouts) in a single rigorous study\",\n      \"pmids\": [\"16201016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression in Trichoplusia ni cells; radioiodinated ATR binding assay; BKA and ADP competition binding\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro ligand binding with functional reconstitution, single lab\",\n      \"pmids\": [\"16060289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry analysis of SIRT4 co-immunoprecipitates; mitochondrial localization by fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP/MS identification without further mechanistic dissection of the SLC25A6 interaction\",\n      \"pmids\": [\"17715127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Reconstitution into liposomes; transport assays after heterologous expression and purification (as part of systematic SLC25 family characterization)\",\n      \"journal\": \"Molecular aspects of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in liposomes with transport assay, part of systematic family characterization reviewed across multiple studies\",\n      \"pmids\": [\"23266187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, proteomics, loss-of-function with defined mitochondrial permeability phenotype, in vivo validation\",\n      \"pmids\": [\"32156782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; gain- and loss-of-function (overexpression/knockdown); mPTP opening assay; mitochondrial membrane potential measurement; apoptosis assay; in vivo AKI mouse model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, multiple orthogonal functional assays, in vivo validation\",\n      \"pmids\": [\"37182101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo zebrafish model with pharmacological epistasis, supported by human cohort data\",\n      \"pmids\": [\"37495650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown and pharmacological inhibition; mitochondrial function assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP without mechanistic dissection of SLC25A6's specific role in the complex\",\n      \"pmids\": [\"37034225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; EFHD1 overexpression/knockdown with mPTP opening assay and drug sensitivity readouts; pharmacological ANT3 conformational inhibitors (CATR and BKA)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, pharmacological epistasis with specific ANT3 ligands, gain/loss-of-function with defined mPTP and chemoresistance phenotypes\",\n      \"pmids\": [\"38795203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay (K48 linkage-specific); MRPL13 knockdown/overexpression; mPTP opening, ROS, OXPHOS, and cytochrome c release assays; in vivo xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, mechanistic ubiquitination assay, multiple orthogonal mitochondrial phenotypic readouts, in vivo validation\",\n      \"pmids\": [\"40841355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot; VDAC1 siRNA knockdown; mPTP opening assay; mitochondrial membrane potential, ROS, and ATP measurement; apoptosis assay\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — indirect regulatory relationship inferred from knockdown and drug treatment without direct binding evidence between VDAC1 and SLC25A6\",\n      \"pmids\": [\"40060777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; XPNPEP2 knockout in vivo and in vitro; SLC25A6 silencing; SIAH1 ubiquitination assay; mitochondrial function assays; angiogenesis (tube formation, migration) assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, ubiquitination mechanism identified, loss-of-function with defined angiogenic phenotype; single lab\",\n      \"pmids\": [\"41573684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis (T126A); mitofission markers; caspase-3 activity indicator (single-cell monitoring); mitofission inhibitor epistasis; in vivo xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — co-IP, mutagenesis defining binding residue, pharmacological epistasis, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"42020360\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A6 (ANT3) is an inner mitochondrial membrane ADP/ATP antiporter located in the pseudoautosomal region that escapes X-inactivation; it regulates mitochondrial membrane permeability transition pore (mPTP) opening through conformational states controlled by interacting partners including MRPL12 (stabilizing), mortalin/HSPA9 (inhibiting ANT3–CypD interaction), EFHD1 (inhibiting conformational change), and MRPL13 (promoting K48-ubiquitin-dependent SLC25A6 degradation); additionally, SLC25A6 directly binds MIC60 to disrupt the MICOS complex and promote mitofission under metabolic stress, is targeted by viral proteins (influenza PB1-F2) to induce apoptosis, modulates cardiac repolarization (QTc interval) upstream of mitochondrial KATP channels, and is regulated at the protein level by XPNPEP2 via SIAH1-mediated ubiquitination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC25A6 (ANT3) is an inner mitochondrial membrane ADP/ATP translocase whose conformational state serves as a central regulatory node for mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane integrity, and apoptosis. SLC25A6 binds ADP, atractyloside, and bongkrekic acid with affinities comparable to bovine ANT [PMID:16060289]; its interaction with cyclophilin D promotes mPTP opening, a process opposed by mortalin/HSPA9 chaperone binding and ERK signaling [PMID:32156782], and modulated by EFHD1 and MRPL12, which stabilize a closed ANT3 conformation to suppress mPTP [PMID:38795203, PMID:37182101]. SLC25A6 abundance is controlled by K48-linked ubiquitin-dependent degradation mediated by MRPL13 and SIAH1 [PMID:40841355, PMID:41573684], and SLC25A6 directly interacts with MIC60 of the MICOS complex to competitively displace MIC19, linking glutamine metabolic stress to mitochondrial fission and intrinsic apoptosis [PMID:42020360]. Beyond mitochondrial functions, SLC25A6 gene dosage acts upstream of KATP channels to modulate cardiac repolarization (QTc interval) in zebrafish and human studies [PMID:37495650].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that SLC25A6 is a functional ADP/ATP translocase and a target for viral exploitation: recombinant ANT3 bound canonical inhibitors with conserved affinities, and influenza PB1-F2 was shown to interact directly with ANT3 and VDAC1 to trigger mPTP opening and cytochrome c release, connecting SLC25A6 to apoptotic mitochondrial permeability for the first time.\",\n      \"evidence\": \"Radioligand binding in insect cell mitochondria; GST pulldown/MS plus isolated mitochondria reconstitution with PB1-F2\",\n      \"pmids\": [\"16060289\", \"16201016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No endogenous mammalian binding partners of ANT3 controlling mPTP had been identified\",\n        \"Conformational mechanism by which ANT3 opens mPTP was undefined\",\n        \"Isoform-specific roles versus ANT1/ANT2 not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The chaperone mortalin (HSPA9) was identified as a physiological ANT3 binding partner that suppresses ANT3–cyclophilin D interaction, revealing a signaling axis (MEK-ERK → mortalin → ANT3–CypD) that tunes mitochondrial permeability in cancer cells.\",\n      \"evidence\": \"Proteomics screen, reciprocal co-IP, mortalin depletion/overexpression with permeability and viability readouts, in vivo tumor model\",\n      \"pmids\": [\"32156782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of mortalin–ANT3 interaction unknown\",\n        \"Whether mortalin regulates ANT1/ANT2 similarly was not tested\",\n        \"Direct phosphorylation events linking ERK to ANT3–CypD not mapped\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple regulators of ANT3 conformation were identified: MRPL12 stabilizes ANT3 to keep mPTP closed in renal tubular cells; EFHD1 directly inhibits ANT3 conformational change to suppress mPTP in cancer; and SLC25A6 gene dosage was shown to act upstream of KATP channels in cardiac repolarization, revealing a non-canonical role outside classical mPTP biology.\",\n      \"evidence\": \"Co-IP with loss/gain of function and mPTP assays (MRPL12, EFHD1); pharmacological epistasis with CATR/BKA (EFHD1); zebrafish knockdown/overexpression with KATP channel modulators (cardiac)\",\n      \"pmids\": [\"37182101\", \"38795203\", \"37495650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"MRPL12 and EFHD1 binding sites on ANT3 not mapped; potential overlap unknown\",\n        \"Molecular mechanism linking ANT3 to KATP channel activity is undefined\",\n        \"EFHD1 and MRPL12 findings each from single labs\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SLC25A6 protein levels were found to be regulated by ubiquitin-dependent degradation: MRPL13 promotes K48-linked ubiquitination and degradation of SLC25A6 to reduce mPTP opening in ovarian cancer, while SIAH1-mediated degradation of SLC25A6 downstream of XPNPEP2 loss impairs mitochondrial function and angiogenesis.\",\n      \"evidence\": \"Co-IP, K48-ubiquitination assays, knockdown/overexpression, xenograft models (MRPL13); XPNPEP2 KO with SIAH1 pathway dissection, tube formation and vascular phenotype (XPNPEP2/SIAH1)\",\n      \"pmids\": [\"40841355\", \"41573684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ligase directly ubiquitinating ANT3 in the MRPL13 pathway was not identified\",\n        \"Whether SIAH1 and MRPL13 pathways converge on the same ubiquitination site is unknown\",\n        \"Each finding from a single lab; independent replication pending\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"SLC25A6 was linked to mitochondrial dynamics through direct interaction with MIC60 of the MICOS complex: SLC25A6 competitively displaces MIC19 from MIC60, destabilizing cristae junctions and promoting mitochondrial fission and intrinsic apoptosis under glutamine deprivation stress, with the T126A mutation abolishing this interaction.\",\n      \"evidence\": \"Co-IP, T126A site-directed mutagenesis, mitochondrial fission markers, caspase-3 activity, in vivo xenograft\",\n      \"pmids\": [\"42020360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of ANT3–MIC60 interaction and how T126 mediates binding not resolved\",\n        \"Whether ANT1/ANT2 share MIC60 binding capacity untested\",\n        \"Single-lab finding; independent validation needed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of ANT3 conformational switching that gates mPTP, isoform-specific roles relative to ANT1/ANT2, the molecular link between ANT3 and KATP channel regulation in the heart, and whether the multiple identified binding partners (mortalin, MRPL12, EFHD1, MRPL13, MIC60) compete for overlapping or distinct interaction surfaces on ANT3.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of ANT3 in complex with any regulatory partner\",\n        \"Isoform-specific knockout studies in mammalian models lacking\",\n        \"Integration of ubiquitin-mediated turnover with conformational regulation not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HSPA9\",\n      \"PPIF\",\n      \"MRPL12\",\n      \"MRPL13\",\n      \"EFHD1\",\n      \"IMMT\",\n      \"VDAC1\",\n      \"XPNPEP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the genomic identity and escape from X-inactivation resolved why ANT3 is expressed from both sex chromosomes and varies with sex-chromosome dosage.\",\n      \"evidence\": \"Genomic cloning, FISH mapping to PAR at Xp22.3, and transcription analysis from active/inactive X and Y chromosomes\",\n      \"pmids\": [\"8486369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of dosage variation were not explored\", \"No protein-level expression quantification across tissues\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"16060289\", \"16201016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transport kinetics of recombinant human ANT3 not measured in liposomes at this stage\", \"Structural basis of PB1-F2 interaction unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Heterologous expression, purification, and transport assay in liposomes as part of SLC25 family characterization\",\n      \"pmids\": [\"23266187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No isoform-specific kinetic comparison among ANT1-4 under identical conditions\", \"Post-translational regulation of transport activity not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal co-IP of mortalin–ANT3 and ANT3–CypD; mortalin depletion causing lethal mitochondrial permeabilization in BRAF-V600E cells; in vivo tumor models\",\n      \"pmids\": [\"32156782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation site on ANT3 downstream of MEK-ERK not identified\", \"Structural basis of mortalin–ANT3 interaction unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"37182101\", \"37495650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP; EFHD1 overexpression/knockdown with mPTP assays; pharmacological reversal with CATR and BKA in osteosarcoma cells\",\n      \"pmids\": [\"38795203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EFHD1 binding domain on ANT3 not mapped\", \"Whether EFHD1 regulation occurs in non-cancer tissues is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal co-IP; K48-ubiquitin linkage assay for MRPL13–SLC25A6; XPNPEP2 KO with SIAH1 ubiquitination assay; mitochondrial function, angiogenesis, and xenograft models\",\n      \"pmids\": [\"40841355\", \"41573684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP; T126A mutagenesis abolishing MIC60 binding and mitofission; single-cell caspase-3 monitoring; mitofission inhibitor epistasis; in vivo xenograft\",\n      \"pmids\": [\"42020360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2, 4, 5, 6, 9, 10, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 5, 6, 9, 10, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"Permeability transition pore complex (mPTP/PTPC)\"\n    ],\n    \"partners\": [\n      \"HSPA9\",\n      \"PPIF\",\n      \"MRPL12\",\n      \"EFHD1\",\n      \"MRPL13\",\n      \"MIC60\",\n      \"VDAC1\",\n      \"XPNPEP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}