{"gene":"SLC25A6","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2005,"finding":"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.","method":"GST pulldown, mass spectrometry, purified mitochondria assays (cytochrome c release, membrane potential measurement), caspase 3 cleavage assay, PTPC inhibitor experiments","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — GST pulldown with MS identification plus multiple orthogonal functional assays (cytochrome c release, membrane potential, caspase activation, pharmacological inhibition) in a single rigorous study","pmids":["16201016"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Ectopic expression of histidine-tagged ANT-3 in Trichoplusia ni cells, radioiodinated ATR binding assay, comparison with bovine heart mitochondria preparations","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ligand-binding assay with recombinant human ANT-3, multiple ligands tested, single lab","pmids":["16060289"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Proteomics screening, co-immunoprecipitation, mortalin knockdown/depletion, MEK-ERK pathway manipulation, mitochondrial permeability assays, in vitro and in vivo tumor cell proliferation assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, proteomics identification of ANT3 as mortalin substrate, pathway epistasis with MEK-ERK, multiple orthogonal functional assays, in vitro and in vivo validation","pmids":["32156782"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, MRPL12 overexpression in renal tubular epithelial cells, hypoxia/reoxygenation model, MPTP opening assay, apoptosis assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing direct interaction, functional rescue by MRPL12 overexpression, MPTP and apoptosis readouts; single lab","pmids":["37182101"],"is_preprint":false},{"year":2023,"finding":"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.","method":"In vivo zebrafish slc25a6 knockdown and overexpression, QTc interval measurement, pharmacological KATP channel modulation, human cohort correlation analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish loss- and gain-of-function with defined electrophysiological readout and pharmacological epistasis; human data correlational only","pmids":["37495650"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown of PTPMT1, pharmacological PTPMT1 inhibition, mitochondrial function assays","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP demonstrating interaction, no mechanistic dissection of how SLC25A6-NDUFS2 axis operates, single lab","pmids":["37034225"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, EFHD1 overexpression and knockdown, mPTP opening assay, cisplatin sensitivity assay, pharmacological ANT3 conformational inhibitors (CATR and BKA)","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional genetic manipulation, pharmacological rescue using ANT3-specific conformational inhibitors confirming mechanistic link; single lab","pmids":["38795203"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation, site-directed mutagenesis (T126A), mitochondrial fragmentation assays, apoptosis assays, in vitro and in vivo cancer models, mitofission inhibitor experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding established by Co-IP, mutagenesis identifies specific interaction residue (T126), multiple orthogonal functional readouts, in vivo validation; single lab","pmids":["42020360"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation, XPNPEP2 and SLC25A6 knockdown/overexpression, SIAH1 ubiquitination assay, in vitro and in vivo angiogenesis assays, mitochondrial function assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic epistasis (XPNPEP2→SIAH1→SLC25A6), multiple functional readouts; single lab","pmids":["41573684"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct deacetylation assay identifying SIRT3 as the eraser for SLC25A6 acetylation, protein stability assay, genetic epistasis rescue, multiple orthogonal methods; single lab","pmids":["42260555"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48-ubiquitination assay identifying ubiquitin linkage type, multiple functional readouts; single lab","pmids":["40841355"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Western blotting, VDAC1 knockdown, mPTP assay, mitochondrial membrane potential assay, ROS and ATP measurements, LPS-inflammatory injury model","journal":"ACS omega","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological and knockdown approach, downstream relationship of SLC25A6 to VDAC1 inferred from expression data without direct mechanistic dissection; single lab","pmids":["40060777"],"is_preprint":false}],"current_model":"SLC25A6 (ANT3) is a mitochondrial inner membrane ADP/ATP translocase that is a central regulator of the mitochondrial permeability transition pore (mPTP): its conformational state (controlled by interactions with partners including mortalin/HSPA9, MRPL12, EFHD1, CypD, MRPL13, and MIC60) determines mPTP open/closed status, cytochrome c release, and cell survival; it is post-translationally regulated by SIRT3-mediated deacetylation (promoting stability) and SIAH1/MRPL13-mediated ubiquitination (promoting degradation); it binds viral PB1-F2 to sensitize cells to apoptosis; it interacts with the MICOS complex component MIC60 to drive mitofission; and its dosage regulates cardiac QTc interval via KATP channel-dependent repolarization."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2005,"claim":"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","pmids":["16060289"],"confidence":"Medium","gaps":["No structural model of the human isoform","Transport kinetics in a defined reconstituted system not reported","Does not address mPTP gating role"]},{"year":2005,"claim":"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","pmids":["16201016"],"confidence":"High","gaps":["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"]},{"year":2020,"claim":"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","pmids":["32156782"],"confidence":"High","gaps":["Does not define the ANT3 conformational state mortalin enforces","CypD binding site on ANT3 unmapped","Generality beyond BRAF-mutant context unknown"]},{"year":2023,"claim":"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","pmids":["37182101"],"confidence":"Medium","gaps":["Direct binding region on ANT3 not defined","Single lab","Relationship to mortalin/CypD axis not tested"]},{"year":2023,"claim":"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","pmids":["37495650"],"confidence":"Medium","gaps":["Mechanism linking translocase activity to KATP channel state unknown","Human data correlational only","Cell type mediating the effect not identified"]},{"year":2023,"claim":"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","pmids":["37034225"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation or mechanistic dissection","How the SLC25A6-NDUFS2 axis operates is undefined","Functional consequence for ANT3 unknown"]},{"year":2024,"claim":"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","pmids":["38795203"],"confidence":"Medium","gaps":["EFHD1 binding site on ANT3 not mapped","Single lab","Interplay with other mPTP-restraining partners not tested"]},{"year":2025,"claim":"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","pmids":["40841355"],"confidence":"Medium","gaps":["E3 ligase mediating MRPL13-directed ubiquitination not identified","Single lab","Relationship to MRPL12 stabilizing role unresolved"]},{"year":2025,"claim":"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","pmids":["40060777"],"confidence":"Low","gaps":["SLC25A6-VDAC1 relationship inferred from expression, not direct mechanism","No demonstration of physical interaction","Single lab"]},{"year":2026,"claim":"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","pmids":["42020360"],"confidence":"High","gaps":["How this function is normally regulated unknown","Relationship between MICOS disruption and mPTP gating not integrated","Single lab"]},{"year":2026,"claim":"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","pmids":["42260555","41573684"],"confidence":"High","gaps":["Acetylation site(s) on ANT3 not mapped","Integration of deacetylation versus ubiquitination control not resolved","Single labs for each axis"]},{"year":null,"claim":"How ANT3 conformational state, MICOS disruption, post-translational modification, and nucleotide transport are mechanistically integrated into a unified model of mPTP control remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,7]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,6,7,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,9]}],"complexes":["mitochondrial permeability transition pore (mPTP/PTPC)"],"partners":["HSPA9","MRPL12","EFHD1","MIC60","MRPL13","SIRT3","XPNPEP2","VDAC1"],"other_free_text":[]}},"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 virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1.","date":"2005","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/16201016","citation_count":296,"is_preprint":false},{"pmid":"10527626","id":"PMC_10527626","title":"The 3D positioning of ANT2 and ANT3 genes within female X chromosome territories correlates with gene activity.","date":"1999","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/10527626","citation_count":101,"is_preprint":false},{"pmid":"8486369","id":"PMC_8486369","title":"A human pseudoautosomal gene encodes the ANT3 ADP/ATP translocase and escapes X-inactivation.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8486369","citation_count":49,"is_preprint":false},{"pmid":"16819836","id":"PMC_16819836","title":"Characterization of the bifunctional aminoglycoside-modifying enzyme ANT(3'')-Ii/AAC(6')-IId from Serratia marcescens.","date":"2006","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16819836","citation_count":48,"is_preprint":false},{"pmid":"32156782","id":"PMC_32156782","title":"Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability.","date":"2020","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/32156782","citation_count":35,"is_preprint":false},{"pmid":"7814020","id":"PMC_7814020","title":"ANT3 and STS are autosomal in prosimian lemurs: implications for the evolution of the pseudoautosomal region.","date":"1995","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7814020","citation_count":31,"is_preprint":false},{"pmid":"37182101","id":"PMC_37182101","title":"MRPL12-ANT3 interaction involves in acute kidney injury via regulating MPTP of tubular epithelial 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11421947","citation_count":11,"is_preprint":false},{"pmid":"23485681","id":"PMC_23485681","title":"Domain dissection and characterization of the aminoglycoside resistance enzyme ANT(3″)-Ii/AAC(6')-IId from Serratia marcescens.","date":"2013","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/23485681","citation_count":10,"is_preprint":false},{"pmid":"38795203","id":"PMC_38795203","title":"EFHD1 promotes osteosarcoma proliferation and drug resistance by inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP) by binding to ANT3.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38795203","citation_count":9,"is_preprint":false},{"pmid":"16060289","id":"PMC_16060289","title":"Ectopic expression of the human adenine nucleotide translocase, isoform 3 (ANT-3). Characterization of ligand binding properties.","date":"2005","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/16060289","citation_count":8,"is_preprint":false},{"pmid":"37495650","id":"PMC_37495650","title":"Dosage of the pseudoautosomal gene SLC25A6 is implicated in QTc interval duration.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37495650","citation_count":7,"is_preprint":false},{"pmid":"37034225","id":"PMC_37034225","title":"PTPMT1 regulates mitochondrial death through the SLC25A6-NDUFS2 axis in pancreatic cancer cells.","date":"2023","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37034225","citation_count":6,"is_preprint":false},{"pmid":"34531844","id":"PMC_34531844","title":"Identification and Characterization of a Novel Aminoglycoside 3''-Nucleotidyltransferase, ANT(3'')-IId, From Acinetobacter lwoffii.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34531844","citation_count":6,"is_preprint":false},{"pmid":"19763879","id":"PMC_19763879","title":"Isolation, nucleotide identification and tissue expression of three novel ovine genes-SLC25A4, SLC25A5 and SLC25A6.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19763879","citation_count":5,"is_preprint":false},{"pmid":"40060777","id":"PMC_40060777","title":"Carvacrol Regulates the Expression of SLC25A6 by Inhibiting VDAC1 to Improve Mitochondrial Function and Reduce LPS-Induced Inflammatory Injury in HMEC-1 Cells.","date":"2025","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/40060777","citation_count":3,"is_preprint":false},{"pmid":"40841355","id":"PMC_40841355","title":"MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40841355","citation_count":2,"is_preprint":false},{"pmid":"40847386","id":"PMC_40847386","title":"Identification of a novel aminoglycoside nucleotidyltransferase ANT(3″)-Ic from Citrobacter telavivum S24.","date":"2025","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40847386","citation_count":1,"is_preprint":false},{"pmid":"42020360","id":"PMC_42020360","title":"Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/42020360","citation_count":0,"is_preprint":false},{"pmid":"41573684","id":"PMC_41573684","title":"XPNPEP2 regulates angiogenesis via modulation of mitochondrial function through SLC25A6.","date":"2026","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41573684","citation_count":0,"is_preprint":false},{"pmid":"42260555","id":"PMC_42260555","title":"SIRT3 regulates mitochondrial metabolism through deacetylation of SLC25A6 to impact gastric cancer progression and drug resistance.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42260555","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12882,"output_tokens":3642,"usd":0.046638,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11273,"output_tokens":3926,"usd":0.077258,"stage2_stop_reason":"end_turn"},"total_usd":0.123896,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"GST pulldown, mass spectrometry, purified mitochondria assays (cytochrome c release, membrane potential measurement), caspase 3 cleavage assay, PTPC inhibitor experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — GST pulldown with MS identification plus multiple orthogonal functional assays (cytochrome c release, membrane potential, caspase activation, pharmacological inhibition) in a single rigorous study\",\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 the natural ligand ADP, with affinities comparable to bovine heart mitochondria, establishing the ligand-binding properties of the human isoform.\",\n      \"method\": \"Ectopic expression of histidine-tagged ANT-3 in Trichoplusia ni cells, radioiodinated ATR binding assay, comparison with bovine heart mitochondria preparations\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ligand-binding assay with recombinant human ANT-3, multiple ligands tested, single lab\",\n      \"pmids\": [\"16060289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics screening, co-immunoprecipitation, mortalin knockdown/depletion, MEK-ERK pathway manipulation, mitochondrial permeability assays, in vitro and in vivo tumor cell proliferation assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, proteomics identification of ANT3 as mortalin substrate, pathway epistasis with MEK-ERK, multiple orthogonal functional assays, in vitro and in vivo validation\",\n      \"pmids\": [\"32156782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, MRPL12 overexpression in renal tubular epithelial cells, hypoxia/reoxygenation model, MPTP opening assay, apoptosis assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing direct interaction, functional rescue by MRPL12 overexpression, MPTP and apoptosis readouts; single lab\",\n      \"pmids\": [\"37182101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo zebrafish slc25a6 knockdown and overexpression, QTc interval measurement, pharmacological KATP channel modulation, human cohort correlation analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish loss- and gain-of-function with defined electrophysiological readout and pharmacological epistasis; human data correlational only\",\n      \"pmids\": [\"37495650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of PTPMT1, pharmacological PTPMT1 inhibition, mitochondrial function assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP demonstrating interaction, no mechanistic dissection of how SLC25A6-NDUFS2 axis operates, single lab\",\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, 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.\",\n      \"method\": \"Co-immunoprecipitation, EFHD1 overexpression and knockdown, mPTP opening assay, cisplatin sensitivity assay, pharmacological ANT3 conformational inhibitors (CATR and BKA)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional genetic manipulation, pharmacological rescue using ANT3-specific conformational inhibitors confirming mechanistic link; single lab\",\n      \"pmids\": [\"38795203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (T126A), mitochondrial fragmentation assays, apoptosis assays, in vitro and in vivo cancer models, mitofission inhibitor experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding established by Co-IP, mutagenesis identifies specific interaction residue (T126), multiple orthogonal functional readouts, in vivo validation; single lab\",\n      \"pmids\": [\"42020360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, XPNPEP2 and SLC25A6 knockdown/overexpression, SIAH1 ubiquitination assay, in vitro and in vivo angiogenesis assays, mitochondrial function assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic epistasis (XPNPEP2→SIAH1→SLC25A6), multiple functional readouts; single lab\",\n      \"pmids\": [\"41573684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assays, cycloheximide chase assays, RNA-seq, SIRT3 and SLC25A6 knockdown/overexpression, in vitro and in vivo tumor models, cisplatin resistance assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct deacetylation assay identifying SIRT3 as the eraser for SLC25A6 acetylation, protein stability assay, genetic epistasis rescue, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"42260555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48-ubiquitination assay identifying ubiquitin linkage type, multiple functional readouts; single lab\",\n      \"pmids\": [\"40841355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Western blotting, VDAC1 knockdown, mPTP assay, mitochondrial membrane potential assay, ROS and ATP measurements, LPS-inflammatory injury model\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological and knockdown approach, downstream relationship of SLC25A6 to VDAC1 inferred from expression data without direct mechanistic dissection; single lab\",\n      \"pmids\": [\"40060777\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A6 (ANT3) is a mitochondrial inner membrane ADP/ATP translocase that is a central regulator of the mitochondrial permeability transition pore (mPTP): its conformational state (controlled by interactions with partners including mortalin/HSPA9, MRPL12, EFHD1, CypD, MRPL13, and MIC60) determines mPTP open/closed status, cytochrome c release, and cell survival; it is post-translationally regulated by SIRT3-mediated deacetylation (promoting stability) and SIAH1/MRPL13-mediated ubiquitination (promoting degradation); it binds viral PB1-F2 to sensitize cells to apoptosis; it interacts with the MICOS complex component MIC60 to drive mitofission; and its dosage regulates cardiac QTc interval via KATP channel-dependent repolarization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #3]. The recombinant human protein binds ADP together with the high-affinity inhibitors atractyloside and bongkrekic acid, establishing its conserved nucleotide-translocase ligand pharmacology [#1]. 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 [#2], MRPL12 stabilizes the pore under physiological conditions [#3], 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 [#6]. Loss of these restraining interactions drives ANT3 conformational change, mPTP opening, and apoptosis [#3, #6]. ANT3 abundance is set by opposing post-translational modifications: SIRT3-mediated deacetylation enhances its stability [#9], whereas SIAH1- and MRPL13-directed K48-linked ubiquitination promote its proteasomal degradation [#8, #10]. 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 [#7]. Influenza PB1-F2 co-opts this axis by binding ANT3 to sensitize cells to mitochondrial permeabilization [#0], and SLC25A6 dosage tunes cardiac repolarization upstream of KATP channels [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"His-tagged human ANT-3 expressed in insect cell mitochondria, radioiodinated atractyloside binding and ADP/BKA competition versus bovine heart mitochondria\",\n      \"pmids\": [\"16060289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the human isoform\", \"Transport kinetics in a defined reconstituted system not reported\", \"Does not address mPTP gating role\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The discovery that influenza PB1-F2 physically binds ANT3 (and VDAC1) linked the translocase to virally driven mitochondrial permeabilization and apoptosis sensitization.\",\n      \"evidence\": \"GST pulldown with MS identification plus cytochrome c release, membrane potential, caspase activation, and PTPC inhibitor assays in purified mitochondria\",\n      \"pmids\": [\"16201016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proteomics, reciprocal Co-IP, mortalin depletion, MEK-ERK manipulation, and mitochondrial permeability assays in BRAF-mutant cells with in vivo validation\",\n      \"pmids\": [\"32156782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the ANT3 conformational state mortalin enforces\", \"CypD binding site on ANT3 unmapped\", \"Generality beyond BRAF-mutant context unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"MRPL12 binding was shown to stabilize the mPTP in renal epithelium, extending the partner-controlled gating model to a physiological injury setting.\",\n      \"evidence\": \"Co-IP, MRPL12 overexpression, hypoxia/reoxygenation model, mPTP and apoptosis assays in renal tubular epithelial cells\",\n      \"pmids\": [\"37182101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding region on ANT3 not defined\", \"Single lab\", \"Relationship to mortalin/CypD axis not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Zebrafish dosage experiments placed SLC25A6 upstream of KATP channel-dependent cardiac repolarization, revealing an organ-level function beyond apoptosis.\",\n      \"evidence\": \"In vivo slc25a6 knockdown/overexpression with QTc measurement and pharmacological KATP modulation, plus correlational human cohort data\",\n      \"pmids\": [\"37495650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking translocase activity to KATP channel state unknown\", \"Human data correlational only\", \"Cell type mediating the effect not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A reported PTPMT1 interaction with SLC25A6 and NDUFS2 hinted at an additional mitochondrial functional axis in pancreatic cancer.\",\n      \"evidence\": \"Co-IP with PTPMT1 knockdown/inhibition and mitochondrial function assays\",\n      \"pmids\": [\"37034225\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or mechanistic dissection\", \"How the SLC25A6-NDUFS2 axis operates is undefined\", \"Functional consequence for ANT3 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, EFHD1 overexpression/knockdown, mPTP and cisplatin sensitivity assays, and CATR/BKA conformational inhibitor rescue in osteosarcoma cells\",\n      \"pmids\": [\"38795203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EFHD1 binding site on ANT3 not mapped\", \"Single lab\", \"Interplay with other mPTP-restraining partners not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"MRPL13 was found to drive K48-linked ubiquitination of SLC25A6, defining degradative control of ANT3 abundance that suppresses mPTP opening in ovarian cancer.\",\n      \"evidence\": \"Co-IP, K48-linkage-specific ubiquitination assay, MRPL13 knockdown/overexpression, mPTP and cytochrome c release assays with in vivo models\",\n      \"pmids\": [\"40841355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating MRPL13-directed ubiquitination not identified\", \"Single lab\", \"Relationship to MRPL12 stabilizing role unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Carvacrol-driven upregulation of SLC25A6 downstream of VDAC1 inhibition associated ANT3 levels with improved mitochondrial function under inflammatory injury.\",\n      \"evidence\": \"Western blot, VDAC1 knockdown, mPTP/membrane potential/ROS/ATP assays in LPS-treated endothelial cells\",\n      \"pmids\": [\"40060777\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"SLC25A6-VDAC1 relationship inferred from expression, not direct mechanism\", \"No demonstration of physical interaction\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, T126A site-directed mutagenesis, mitochondrial fragmentation and apoptosis assays, mitofission inhibitors, in vivo cancer models\",\n      \"pmids\": [\"42020360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How this function is normally regulated unknown\", \"Relationship between MICOS disruption and mPTP gating not integrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, acetylation and CHX-chase stability assays, SIAH1 ubiquitination assay, epistasis rescue, and in vitro/in vivo cancer and angiogenesis models\",\n      \"pmids\": [\"42260555\", \"41573684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation site(s) on ANT3 not mapped\", \"Integration of deacetylation versus ubiquitination control not resolved\", \"Single labs for each axis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANT3 conformational state, MICOS disruption, post-translational modification, and nucleotide transport are mechanistically integrated into a unified model of mPTP control remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 6, 7, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [\"mitochondrial permeability transition pore (mPTP/PTPC)\"],\n    \"partners\": [\"HSPA9\", \"MRPL12\", \"EFHD1\", \"MIC60\", \"MRPL13\", \"SIRT3\", \"XPNPEP2\", \"VDAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}