{"gene":"SLC25A11","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2011,"finding":"The C. elegans ortholog MISC-1 (and mammalian OGC/SLC25A11) controls mitochondrial morphology (fusion and fission) and participates in apoptosis induction through interaction with anti-apoptotic proteins CED-9/Bcl-xL and pro-apoptotic ANT, as demonstrated by pull-down experiments; knockdown of misc-1/OGC induces apoptosis via the caspase cascade, and MISC-1 controls apoptosis through the LIN-35/Rb-like protein pathway.","method":"Pull-down assays (MISC-1/OGC interaction with CED-9, Bcl-xL, ANT), genetic epistasis (LIN-35/Rb pathway), RNAi knockdown with apoptosis readout, transmission electron microscopy (mitochondrial cristae morphology)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pull-down, genetic epistasis, TEM morphology, multiple orthogonal methods in two organisms","pmids":["21448454"],"is_preprint":false},{"year":2007,"finding":"Structural characterization of all six transmembrane segments (TMS I–VI) of OGC/SLC25A11 by CD and NMR spectroscopy revealed alpha-helical structures in TFE/water and SDS micelles; the helical structures are compatible with a homology model based on the ADP/ATP carrier X-ray structure, supporting the six-helix bundle architecture of the carrier.","method":"CD and NMR spectroscopy of synthetic transmembrane peptides; homology modeling based on ADP/ATP carrier crystal structure","journal":"The Italian journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 method (NMR structural characterization) but single lab, peptide fragments only, no mutagenesis functional validation","pmids":["19192628"],"is_preprint":false},{"year":2018,"finding":"Germline loss-of-function mutations in SLC25A11 (encoding the mitochondrial 2-oxoglutarate/malate carrier) predispose to metastatic paraganglioma. Loss of SLC25A11 function (via CRISPR-Cas9 knockout in mouse chromaffin cells) produces pseudohypoxic and hypermethylator phenotypes comparable to those in SDHx- and FH-related tumors, indicating SLC25A11 acts as a tumor suppressor gene through disruption of mitochondrial metabolite transport.","method":"Whole-exome sequencing, loss of heterozygosity analysis, CRISPR-Cas9 knockout in mouse chromaffin cells with metabolic and epigenetic phenotyping","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with defined molecular phenotypes (pseudohypoxia, hypermethylation), replicated across seven patients and cell model","pmids":["29431636"],"is_preprint":false},{"year":2019,"finding":"SLC25A11 transports cytosolic NADH into mitochondria in the form of malate (as part of the malate-aspartate shuttle), and cancer cells (NSCLC and melanoma) exhibit higher cytosolic-to-mitochondrial NADH ratios and higher SLC25A11 expression than normal cells. Knockdown of SLC25A11 impairs mitochondrial ATP production and inhibits cancer cell growth, while heterozygous Slc25a11 knockout mice suppress KRAS-driven lung tumor formation.","method":"siRNA knockdown with ATP/NADH measurement, metabolite profiling, in vivo KRAS lung tumor cross-breeding model with heterozygous Slc25a11 knockout mice","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 — KD with defined metabolic phenotype (ATP, NADH), in vivo genetic model, multiple cancer cell lines","pmids":["30686754"],"is_preprint":false},{"year":2024,"finding":"Neutrophil extracellular traps (NETs) decrease the stability and dimerization of SLC25A11, assessed by blue native PAGE, leading to depletion of mitochondrial glutathione (mitoGSH), which induces ferroptosis in smooth muscle cells and promotes abdominal aortic aneurysm formation. SLC25A11 functions as a mitochondrial glutathione transporter whose dimerization state controls mitoGSH levels.","method":"Blue native PAGE (SLC25A11 dimerization), western blotting/immunofluorescence, in vitro SMC ferroptosis assay, in vivo angiotensin II AAA mouse model with PAD4 KO, transmission electron microscopy","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 — direct biochemical measurement of SLC25A11 dimerization, multiple in vitro and in vivo models with defined ferroptosis phenotype","pmids":["38796028"],"is_preprint":false},{"year":2025,"finding":"N-phenylmaleimide (KN612) inhibits SLC25A11 (the αKG/malate antiporter component of the malate-aspartate shuttle in GBM), reducing oxygen consumption rate, ATP levels, mitochondrial activity, and cell viability in glioblastoma tumorspheres, and decreasing stemness and invasion; in vivo orthotopic xenograft treatment reduced tumor size and prolonged survival.","method":"siRNA knockdown, pharmacological inhibition (KN612), oxygen consumption rate measurement, ATP assay, in vivo orthotopic xenograft mouse model, transcriptomic analysis","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — KD plus pharmacological inhibition with defined bioenergetic readouts and in vivo validation, single lab","pmids":["40405188"],"is_preprint":false},{"year":2025,"finding":"OTUD1 deubiquitinates and stabilizes SLC25A11 protein, thereby increasing mitochondrial ROS and apoptosis in nasopharyngeal carcinoma cells; loss of OTUD1-mediated SLC25A11 stabilization enhances radioresistance, and this axis is regulated upstream by TFAP2C methylation.","method":"Co-immunoprecipitation (OTUD1-SLC25A11 interaction), deubiquitination assay, siRNA knockdown/overexpression with ROS and apoptosis readouts, in vitro and in vivo radioresistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and deubiquitination assay establishing PTM (ubiquitination) regulation of SLC25A11, single lab","pmids":["40664662"],"is_preprint":false},{"year":2025,"finding":"Chronic hypoxia increases N6-methyladenosine (m6A) modification on the SLC25A11 3'UTR via METTL3, with m6A-binding protein YTHDF2 binding to the SLC25A11 3'UTR, leading to decreased SLC25A11 expression and subsequent ferroptosis and mitochondrial dysfunction in cardiomyocytes. SLC25A11 overexpression inhibits chronic hypoxia-induced ferroptosis; the METTL3 inhibitor STM2457 reverses this by restoring SLC25A11 levels.","method":"m6A methylation assay (MeRIP), YTHDF2 RIP (RNA immunoprecipitation), SLC25A11 overexpression/shRNA in cardiomyocytes, cell viability/ferroptosis assays, hypoxic mouse model","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 — RIP establishing m6A reader-SLC25A11 mRNA interaction, genetic rescue experiments, in vivo model; single lab","pmids":["41404734"],"is_preprint":false},{"year":2025,"finding":"OGC (Slc25a11) silencing in RPE cells aggravates TGF-β2-induced epithelial-to-mesenchymal transition (EMT) via pSmad2/3 upregulation dependent on PI3K/AKT signaling, and reduces mitochondrial respiration and mitoGSH; conversely, OGC overexpression attenuates EMT, cell proliferation, and migration. In vivo, OGC+/− mice show significantly augmented subretinal fibrosis after laser photocoagulation.","method":"siRNA knockdown and overexpression of OGC in ARPE-19 cells, EMT marker measurement (α-SMA, fibronectin, collagen I, E-cadherin, Slug), mitochondrial bioenergetics assay, PI3K/AKT/Smad2/3 pathway analysis, OCT and immunostaining in OGC+/− mice","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 — KD/OE with pathway placement (PI3K/AKT/Smad), in vivo heterozygous mouse model; single lab","pmids":["41147690"],"is_preprint":false},{"year":2025,"finding":"SLC25A11 inhibition leads to accumulation of TCA-related metabolites, loss of mitochondrial membrane potential, and mitochondrial lipid ROS accumulation. Loss of SLC25A11 reduces NRF2 expression/nuclear translocation and its interaction with ferroptosis suppressor FSP1, activating lipid peroxidation molecules ACSL4, LPCAT3, and PEBP1 to induce ferroptosis in biliary tract cancer cells.","method":"SLC25A11 knockdown/overexpression, RNA sequencing, mitochondrial membrane potential assay, lipid ROS imaging, NRF2-FSP1 co-immunoprecipitation, ACSL4/LPCAT3/PEBP1 protein expression, ferrostatin-1 rescue, in vivo tumor model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — KD with RNA-seq pathway placement, Co-IP for NRF2-FSP1 interaction, ferrostatin-1 rescue; single lab","pmids":["41514409"],"is_preprint":false},{"year":2025,"finding":"SLC25A11 (the mitochondrial αKG/malate antiporter) is required for KDM2A-dependent reduction of rRNA transcription: inhibition of SLC25A11 by N-phenylmaleimide or its knockdown blocks the AOA (aspartate transaminase inhibitor)-induced decrease in intracellular αKG, preventing KDM2A from demethylating H3K36me2 at the rRNA gene promoter. Supplementation with cell-permeable dimethyl-αKG restores KDM2A activity inhibited by SLC25A11 blockade, linking SLC25A11-mediated αKG export from mitochondria to epigenetic regulation of rRNA transcription.","method":"N-phenylmaleimide pharmacological inhibition of SLC25A11, siRNA knockdown of SLC25A11, intracellular ATP measurement, H3K36me2 ChIP at rRNA gene promoter, dimethyl-αKG supplementation rescue experiment in MCF-7 cells","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic inhibition with chromatin (ChIP) readout and metabolite rescue; single lab","pmids":["41227300"],"is_preprint":false},{"year":2025,"finding":"A forward genetic screen using an αKG biosensor identified a sequential inter-organelle pathway in which GPT2 transaminase and SLC25A11 transporter together supply nuclear αKG required for chromatin demethylation; loss of this pathway in a mouse model of GPT2 deficiency alters chromatin methylation in the developing brain.","method":"αKG transcriptional biosensor (NtcA-based), CRISPR genetic screen, GPT2-deficient mouse model, chromatin methylation analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — biosensor-coupled genetic screen with in vivo mouse model validation; preprint, single study","pmids":["bio_10.1101_2025.04.06.647450"],"is_preprint":true}],"current_model":"SLC25A11 encodes the inner mitochondrial membrane 2-oxoglutarate/malate antiporter (OGC) that exchanges cytosolic malate for mitochondrial 2-oxoglutarate across six transmembrane α-helices; it functions as a core component of the malate-aspartate shuttle to transfer cytosolic NADH equivalents into mitochondria for ATP production, transports glutathione into the mitochondrial matrix (maintaining mitoGSH and preventing ferroptosis), and supplies nuclear α-ketoglutarate for chromatin demethylation, while its protein stability is regulated by OTUD1-mediated deubiquitination and METTL3-mediated m6A modification of its mRNA; loss-of-function activates pseudohypoxic/hypermethylator phenotypes and acts as a tumor suppressor in paraganglioma."},"narrative":{"teleology":[{"year":2007,"claim":"Determining whether the OGC adopts the predicted six-transmembrane-helix architecture was essential for placing it within the mitochondrial carrier family; CD/NMR spectroscopy of all six transmembrane segments confirmed α-helical structures consistent with the ADP/ATP carrier fold.","evidence":"CD and NMR spectroscopy of synthetic OGC transmembrane peptides with homology modeling","pmids":["19192628"],"confidence":"Medium","gaps":["No full-length structure determined","No mutagenesis to test functional residues","Peptide fragments studied in detergent/TFE rather than a lipid bilayer"]},{"year":2011,"claim":"Whether SLC25A11 participates in processes beyond metabolite transport was unclear; interaction with anti-apoptotic CED-9/Bcl-xL and pro-apoptotic ANT, and genetic epistasis with the LIN-35/Rb pathway, established a role for OGC in mitochondrial morphology control and apoptosis induction.","evidence":"Pull-down assays, RNAi knockdown with apoptosis scoring, TEM, genetic epistasis in C. elegans and mammalian cells","pmids":["21448454"],"confidence":"High","gaps":["Whether the apoptotic role is conserved in all mammalian tissues remains unresolved","No direct measurement of transport activity during apoptosis"]},{"year":2018,"claim":"The question of whether SLC25A11 loss could be oncogenic was answered when germline loss-of-function mutations were found in paraganglioma patients and CRISPR knockout reproduced pseudohypoxic and hypermethylator phenotypes, establishing SLC25A11 as a tumor suppressor gene analogous to SDHx/FH.","evidence":"Whole-exome sequencing of seven patients, LOH analysis, CRISPR-Cas9 knockout in mouse chromaffin cells with metabolic/epigenetic profiling","pmids":["29431636"],"confidence":"High","gaps":["No rescue experiment restoring SLC25A11 in knockout cells","Penetrance and spectrum of associated tumors not fully defined"]},{"year":2019,"claim":"How SLC25A11 supports tumor bioenergetics was clarified by showing that cancer cells rely on its malate-aspartate shuttle activity for mitochondrial NADH import and ATP production; knockdown impaired ATP synthesis, and heterozygous Slc25a11 knockout suppressed KRAS-driven lung tumorigenesis in vivo.","evidence":"siRNA knockdown with ATP/NADH measurement in NSCLC/melanoma lines, heterozygous Slc25a11 knockout crossed with KRAS-driven lung tumor model","pmids":["30686754"],"confidence":"High","gaps":["Whether other shuttle components compensate at different stoichiometries is unknown","No direct flux measurement of malate/oxoglutarate exchange rates"]},{"year":2024,"claim":"Whether SLC25A11 directly controls mitochondrial glutathione was uncertain; demonstration that NETs destabilize SLC25A11 dimers, deplete mitoGSH, and induce ferroptosis in smooth muscle cells established a non-canonical transport function—mitochondrial glutathione import—governed by SLC25A11 oligomeric state.","evidence":"Blue native PAGE (dimerization), mitoGSH quantification, ferroptosis assays in SMCs, angiotensin II AAA mouse model with PAD4 KO","pmids":["38796028"],"confidence":"High","gaps":["Direct reconstitution of GSH transport by purified SLC25A11 not yet performed","Structural basis of how dimerization controls GSH versus α-KG transport is unknown"]},{"year":2025,"claim":"Multiple 2025 studies converged on ferroptosis as a downstream consequence of SLC25A11 loss: m6A-mediated mRNA degradation by METTL3/YTHDF2 reduces SLC25A11 in hypoxic cardiomyocytes causing ferroptosis, and SLC25A11 depletion in biliary tract cancer activates ACSL4/LPCAT3/PEBP1 lipid peroxidation via NRF2-FSP1 axis collapse, consolidating ferroptosis as a central phenotype of SLC25A11 deficiency.","evidence":"MeRIP and RIP for m6A/YTHDF2-SLC25A11 mRNA interaction with genetic rescue in cardiomyocytes; NRF2-FSP1 Co-IP and ferrostatin-1 rescue in biliary tract cancer cells; in vivo models","pmids":["41404734","41514409"],"confidence":"Medium","gaps":["Whether m6A regulation of SLC25A11 occurs in non-cardiac tissues is untested","Relative contribution of GSH depletion versus α-KG imbalance to ferroptosis not dissected"]},{"year":2025,"claim":"How SLC25A11 protein levels are maintained was answered by showing OTUD1 deubiquitinates SLC25A11, stabilizing it; loss of this axis increases radioresistance in nasopharyngeal carcinoma through reduced mitochondrial ROS and apoptosis.","evidence":"Co-IP and deubiquitination assay for OTUD1-SLC25A11, siRNA/overexpression with ROS and apoptosis readouts, in vivo radioresistance model","pmids":["40664662"],"confidence":"Medium","gaps":["Ubiquitination sites on SLC25A11 not mapped","E3 ligase responsible for SLC25A11 ubiquitination not identified"]},{"year":2025,"claim":"The question of whether SLC25A11-exported α-ketoglutarate feeds nuclear epigenetic reactions was answered: SLC25A11 inhibition blocks α-KG-dependent KDM2A demethylation of H3K36me2 at rRNA gene promoters, and cell-permeable α-KG rescues the defect, establishing a mitochondria-to-nucleus metabolite signaling axis.","evidence":"N-phenylmaleimide inhibition and siRNA knockdown of SLC25A11, H3K36me2 ChIP at rRNA promoter, dimethyl-α-KG rescue in MCF-7 cells","pmids":["41227300"],"confidence":"Medium","gaps":["Whether this axis extends to other α-KG-dependent demethylases (e.g., TET enzymes) via SLC25A11 is untested","Direct measurement of nuclear α-KG pools not performed"]},{"year":2025,"claim":"SLC25A11 haploinsufficiency aggravates EMT and subretinal fibrosis via PI3K/AKT/Smad2/3 signaling, extending the carrier's pathological relevance beyond cancer to fibrotic eye disease.","evidence":"siRNA/overexpression in RPE cells, EMT markers and pathway analysis, OGC+/− mice with laser-induced subretinal fibrosis","pmids":["41147690"],"confidence":"Medium","gaps":["Whether mitoGSH depletion or α-KG imbalance drives the EMT phenotype is not resolved","Single tissue context (RPE cells)"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of SLC25A11 in a lipid membrane, direct reconstitution of GSH transport, identification of the E3 ubiquitin ligase counterpart to OTUD1, and whether the distinct transport cargoes (malate/α-KG versus GSH) use shared or distinct conformational mechanisms.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution cryo-EM or crystal structure of SLC25A11","No reconstituted proteoliposome assay distinguishing GSH from α-KG transport","E3 ligase targeting SLC25A11 for ubiquitination unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[3,4,10,11]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,3,4,5,10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,5,10]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,3,4,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,4,6,7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,5,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10,11]}],"complexes":[],"partners":["OTUD1","YTHDF2","GPT2","BCL2L1","ANT"],"other_free_text":[]},"mechanistic_narrative":"SLC25A11 is the inner mitochondrial membrane 2-oxoglutarate/malate antiporter that operates as a core component of the malate-aspartate shuttle, transferring cytosolic NADH equivalents into mitochondria to sustain oxidative phosphorylation and ATP production [PMID:30686754, PMID:40405188]. Beyond this canonical bioenergetic role, SLC25A11 transports glutathione into the mitochondrial matrix, and disruption of its dimerization depletes mitochondrial GSH and triggers ferroptosis [PMID:38796028, PMID:41514409, PMID:41404734]. SLC25A11-mediated export of α-ketoglutarate from mitochondria supplies the cofactor required for KDM2A-dependent histone demethylation, linking mitochondrial metabolite exchange to epigenetic regulation, and germline loss-of-function mutations in SLC25A11 cause pseudohypoxic/hypermethylator phenotypes that predispose to metastatic paraganglioma [PMID:41227300, PMID:29431636]. Protein stability of SLC25A11 is controlled by OTUD1-mediated deubiquitination, while its mRNA abundance is regulated by METTL3/YTHDF2-dependent m6A modification [PMID:40664662, PMID:41404734]."},"prefetch_data":{"uniprot":{"accession":"Q02978","full_name":"Mitochondrial 2-oxoglutarate/malate carrier protein","aliases":["Solute carrier family 25 member 11","SLC25A11"],"length_aa":314,"mass_kda":34.1,"function":"Catalyzes the transport of 2-oxoglutarate (alpha-oxoglutarate) across the inner mitochondrial membrane in an electroneutral exchange for malate (PubMed:25637873, PubMed:38937634). Can also exchange 2-oxoglutarate for other dicarboxylic acids such as malonate, succinate, maleate and oxaloacetate, although with lower affinity (By similarity). Substrate exchange across the membrane occurs consecutively with one substrate being transported first, then dissociating from the substrate binding site before the second substrate binds for transport in the opposite direction (PubMed:38937634). Does not transport glutathione (PubMed:25637873). Contributes to several metabolic processes, including the malate-aspartate shuttle, the oxoglutarate/isocitrate shuttle, gluconeogenesis from lactate, and nitrogen metabolism (By similarity). Maintains mitochondrial fusion and fission events, and the organization and morphology of cristae (PubMed:21448454). Involved in the regulation of apoptosis (By similarity)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q02978/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC25A11","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC25A11","total_profiled":1310},"omim":[{"mim_id":"618464","title":"PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 6; PPGL6","url":"https://www.omim.org/entry/618464"},{"mim_id":"604165","title":"SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, OXOGLUTARATE CARRIER), MEMBER 11; SLC25A11","url":"https://www.omim.org/entry/604165"},{"mim_id":"168000","title":"PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1; PPGL1","url":"https://www.omim.org/entry/168000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":218.8},{"tissue":"skeletal muscle","ntpm":294.7},{"tissue":"tongue","ntpm":419.8}],"url":"https://www.proteinatlas.org/search/SLC25A11"},"hgnc":{"alias_symbol":["OGC"],"prev_symbol":["SLC20A4"]},"alphafold":{"accession":"Q02978","domains":[{"cath_id":"1.50.40.10","chopping":"20-308","consensus_level":"medium","plddt":89.1361,"start":20,"end":308}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02978","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02978-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02978-F1-predicted_aligned_error_v6.png","plddt_mean":86.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC25A11","jax_strain_url":"https://www.jax.org/strain/search?query=SLC25A11"},"sequence":{"accession":"Q02978","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02978.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02978/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02978"}},"corpus_meta":[{"pmid":"29431636","id":"PMC_29431636","title":"Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29431636","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30686754","id":"PMC_30686754","title":"Loss of SLC25A11 causes suppression of NSCLC and melanoma tumor formation.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/30686754","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21448454","id":"PMC_21448454","title":"MISC-1/OGC links mitochondrial metabolism, apoptosis and insulin secretion.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21448454","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38796028","id":"PMC_38796028","title":"Neutrophil extracellular trap-induced ferroptosis promotes abdominal aortic aneurysm formation via 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via the TFAP2C-OTUD1-SLC25A11 axis.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40664662","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40242210","id":"PMC_40242210","title":"SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome.","date":"2025","source":"Journal of the Endocrine Society","url":"https://pubmed.ncbi.nlm.nih.gov/40242210","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38099467","id":"PMC_38099467","title":"Proteomic analysis by 4D label-free MS-PRM identified that Nptx1, Ptpmt1, Slc25a11, and Cpt1c are involved in diabetes-associated cognitive dysfunction.","date":"2023","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38099467","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19192628","id":"PMC_19192628","title":"Structural characterization of the transmembrane segments of the mitochondrial oxoglutarate carrier (OGC) by NMR spectroscopy.","date":"2007","source":"The Italian journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19192628","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35876985","id":"PMC_35876985","title":"Establishment and characterization of IPS-OGC-C1: a novel induced pluripotent stem cell line from healthy human ovarian granulosa cells.","date":"2022","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/35876985","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41404734","id":"PMC_41404734","title":"METTL3-m6A-SLC25A11 Axis Promotes Chronic Hypoxia-Induced Cardiomyocyte Ferroptosis.","date":"2025","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/41404734","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41147690","id":"PMC_41147690","title":"Deficiency of 2-Oxoglutarate Carrier (Slc25a11) 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cause pseudohypoxic and hypermethylator phenotypes comparable to SDHx/FH-related tumors, demonstrated in CRISPR-Cas9 knockout mouse chromaffin cells.\",\n      \"method\": \"Whole-exome sequencing, CRISPR-Cas9 knockout, loss-of-heterozygosity analysis, metabolic/epigenetic phenotyping\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genomics, CRISPR KO, metabolomics, epigenomics) across multiple patient cases and cellular models\",\n      \"pmids\": [\"29431636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLC25A11 transports cytosolic NADH into mitochondria in the form of malate (via the malate-aspartate shuttle), and its knockdown significantly impairs mitochondrial ATP production and suppresses cancer cell growth while sparing normal cells; heterozygous Slc25a11 knockout mice showed suppressed lung tumor formation.\",\n      \"method\": \"siRNA knockdown, ATP/NADH measurement, metabolite profiling, in vivo mouse cross-breeding with KRASLA2 model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (metabolomics, functional assays, in vivo genetics) in both cell lines and mouse model\",\n      \"pmids\": [\"30686754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MISC-1/OGC (C. elegans/mammalian ortholog of SLC25A11) interacts physically with anti-apoptotic proteins CED-9/Bcl-xL and pro-apoptotic ANT via pull-down; its loss induces apoptosis through the caspase cascade and genetic epistasis places it in the LIN-35/Rb-like pathway; it is also required for proper mitochondrial fusion/fission and morphology.\",\n      \"method\": \"Pull-down assays, genetic epistasis, RNAi knockdown, transmission electron microscopy, apoptosis assays\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pull-downs, genetic epistasis, and orthogonal phenotypic readouts across two organisms\",\n      \"pmids\": [\"21448454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The transmembrane segments (TMS-I through TMS-VI) of OGC/SLC25A11 adopt alpha-helical structures, as characterized by CD and NMR spectroscopy on synthetic peptides in TFE/water and SDS micelles, and a homology model was built based on the ADP/ATP carrier X-ray structure.\",\n      \"method\": \"CD spectroscopy, NMR spectroscopy, homology modeling\",\n      \"journal\": \"The Italian Journal of Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural characterization by NMR, but limited to peptide fragments without full-protein functional validation\",\n      \"pmids\": [\"19192628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NETs (neutrophil extracellular traps) decrease the stability and dimerization of SLC25A11, leading to depletion of mitochondrial glutathione (mitoGSH), which induces ferroptosis of smooth muscle cells and promotes abdominal aortic aneurysm formation.\",\n      \"method\": \"Blue native PAGE (dimerization analysis), Western blotting, immunofluorescence, in vitro SMC ferroptosis assays, Padi4 knockout mouse model, transmission electron microscopy\",\n      \"journal\": \"Free Radical Biology & Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking SLC25A11 dimerization/stability to mitoGSH and ferroptosis, supported by in vivo model\",\n      \"pmids\": [\"38796028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD1 deubiquitinates and stabilizes SLC25A11 protein, and this stabilization leads to increased ROS and apoptosis, enhancing NPC radiosensitivity; the axis is regulated upstream by TFAP2C methylation.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, in vitro and in vivo radiosensitivity assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct deubiquitination assay combined with functional rescue experiments in vitro and in vivo\",\n      \"pmids\": [\"40664662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated m6A modification of the SLC25A11 3'UTR (read by YTHDF2) decreases SLC25A11 expression under chronic hypoxia, leading to mitochondrial dysfunction and ferroptosis in cardiomyocytes; SLC25A11 overexpression inhibits ferroptosis and restores mitochondrial function.\",\n      \"method\": \"m6A sequencing/MeRIP, shRNA and overexpression vectors in AC16 and iPSC-derived cardiomyocytes, METTL3 inhibitor STM2457, iron chelator rescue, hypoxic mouse model\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including m6A mapping, genetic manipulation, pharmacological rescue, and in vivo validation\",\n      \"pmids\": [\"41404734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A11 knockdown reduces mitochondrial membrane potential, accumulates TCA-related metabolites, induces lipid peroxidation/lipid ROS in mitochondria, reduces NRF2 expression and its interaction with FSP1, and activates ACSL4/LPCAT3/PEBP1-dependent ferroptosis in biliary tract cancer cells.\",\n      \"method\": \"SLC25A11 knockdown/overexpression, RNA sequencing, metabolomics, lipid ROS assays, NRF2 localization/interaction assays, in vivo xenograft model\",\n      \"journal\": \"Cellular & Molecular Biology Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking SLC25A11 loss to ferroptosis pathway components with in vivo validation\",\n      \"pmids\": [\"41514409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A11 (the mitochondrial αKG/malate antiporter) supplies α-ketoglutarate to the nucleus via a sequential GPT2 transaminase → SLC25A11 transporter inter-organelle pathway, and this nuclear αKG pool controls chromatin demethylation; SLC25A11 knockdown inhibits AOA-induced KDM2A histone demethylase activity by limiting αKG availability.\",\n      \"method\": \"αKG biosensor genetic screen, SLC25A11 siRNA knockdown, cell-permeable αKG rescue, N-phenylmaleimide pharmacological inhibition, H3K36me2 chromatin assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic screen plus pharmacological and genetic inhibition with epistasis rescue; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.06.647450\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"N-phenylmaleimide (KN612) directly inhibits SLC25A11 antiporter activity within the malate-aspartate shuttle, reducing oxygen consumption rate, ATP levels, and mitochondrial activity in glioblastoma tumorspheres, and suppresses tumor growth in orthotopic xenograft models.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition with KN612, Seahorse metabolic flux analysis, in vivo orthotopic xenograft, transcriptomics\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition confirmed by genetic knockdown with functional metabolic readouts and in vivo validation\",\n      \"pmids\": [\"40405188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A11 loss in RPE cells promotes epithelial-to-mesenchymal transition (EMT) via pSmad2/3 upregulation dependent on PI3K/AKT signaling, reduces mitochondrial glutathione transport and bioenergetics, and augments subretinal fibrosis in vivo in OGC+/- mice.\",\n      \"method\": \"SLC25A11 siRNA/overexpression in ARPE-19 cells, TGF-β2 treatment, EMT marker immunoblotting, mitochondrial respiration (Seahorse), mtGSH measurement, OGC+/- mouse laser photocoagulation model, OCT imaging\",\n      \"journal\": \"Aging Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro assays plus in vivo heterozygous mouse model with defined signaling pathway placement\",\n      \"pmids\": [\"41147690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A11 inhibition by N-phenylmaleimide (NPM) or siRNA knockdown blocks AOA-induced KDM2A histone demethylase activity and reduction of rRNA transcription; this is rescued by cell-permeable dimethyl αKG, demonstrating that SLC25A11 supplies αKG required for KDM2A-mediated H3K36me2 demethylation at rRNA gene promoters.\",\n      \"method\": \"NPM pharmacological inhibition, siRNA knockdown, dimethyl-αKG rescue, H3K36me2 ChIP, rRNA transcription quantification in MCF-7 cells\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological + genetic inhibition with metabolite rescue establishing epistatic pathway position\",\n      \"pmids\": [\"41227300\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A11 is an inner mitochondrial membrane antiporter that exchanges 2-oxoglutarate (α-ketoglutarate) for malate, thereby driving the malate-aspartate shuttle to transfer cytosolic NADH into the mitochondrial matrix for ATP production; it also transports glutathione into mitochondria to maintain mitoGSH levels and suppress ferroptosis, supplies nuclear αKG for KDM2A-dependent chromatin demethylation, interacts with apoptotic regulators (Bcl-xL/ANT), controls mitochondrial morphology through fusion/fission, and functions as a tumor suppressor whose loss triggers pseudohypoxic and hypermethylator phenotypes via impaired metabolite transport.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers.\n\n**CLASSIFICATION:**\n\nCorpus papers (retrieved):\n1. PMID:29431636 — SLC25A11 germline mutations, paraganglioma → KEEP\n2. PMID:30686754 — SLC25A11 NADH transport, NSCLC/melanoma → KEEP\n3. PMID:21448454 — C. elegans MISC-1/OGC, ortholog of mammalian OGC (SLC25A11) → KEEP (ortholog)\n4. PMID:38796028 — SLC25A11 mitoGSH, ferroptosis, AAA → KEEP\n5. PMID:40405188 — KN612 inhibits SLC25A11 in GBM → KEEP\n6. PMID:24589691 — tomato ogc gene (plant) → EXCLUDE (symbol collision, plant)\n7. PMID:40664662 — OTUD1-SLC25A11 axis, NPC radiosensitivity → KEEP\n8. PMID:40242210 — SLC25A11 Carney-Stratakis syndrome → KEEP\n9. PMID:38099467 — Slc25a11 in DACD rat model, proteomics → EXCLUDE (expression correlation, no mechanism)\n10. PMID:19192628 — NMR structural characterization of OGC transmembrane segments → KEEP\n11. PMID:35876985 — iPSC from OGC (ovarian granulosa cells) — \"OGC\" here = ovarian granulosa cell, not the gene → EXCLUDE (alias collision)\n12. PMID:41404734 — METTL3-m6A-SLC25A11 axis, cardiomyocyte ferroptosis → KEEP\n13. PMID:41147690 — OGC/Slc25a11, RPE EMT, subretinal fibrosis → KEEP\n14. PMID:41514409 — SLC25A11, ferroptosis, biliary tract cancer → KEEP\n15. PMID:41227300 — SLC25A11, KDM2A, rRNA transcription → KEEP\n16. bio_10.1101_2024.11.21.624715 — Burkholderia OGC (O-glycosylation cluster) → EXCLUDE (symbol collision, bacterial)\n17. bio_10.1101_2025.04.06.647450 — GPT2/SLC25A11 supply nuclear αKG → KEEP\n\nGene2pubmed curated papers: Most are large interactome/proteome surveys or unrelated biology. I'll note PMID:23266187 (Palmieri SLC25 family review) as relevant context but it's a review. None of the gene2pubmed papers contain primary mechanistic experiments specifically about SLC25A11 beyond what's in the retrieved corpus.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"The C. elegans ortholog MISC-1 (and mammalian OGC/SLC25A11) controls mitochondrial morphology (fusion and fission) and participates in apoptosis induction through interaction with anti-apoptotic proteins CED-9/Bcl-xL and pro-apoptotic ANT, as demonstrated by pull-down experiments; knockdown of misc-1/OGC induces apoptosis via the caspase cascade, and MISC-1 controls apoptosis through the LIN-35/Rb-like protein pathway.\",\n      \"method\": \"Pull-down assays (MISC-1/OGC interaction with CED-9, Bcl-xL, ANT), genetic epistasis (LIN-35/Rb pathway), RNAi knockdown with apoptosis readout, transmission electron microscopy (mitochondrial cristae morphology)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pull-down, genetic epistasis, TEM morphology, multiple orthogonal methods in two organisms\",\n      \"pmids\": [\"21448454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Structural characterization of all six transmembrane segments (TMS I–VI) of OGC/SLC25A11 by CD and NMR spectroscopy revealed alpha-helical structures in TFE/water and SDS micelles; the helical structures are compatible with a homology model based on the ADP/ATP carrier X-ray structure, supporting the six-helix bundle architecture of the carrier.\",\n      \"method\": \"CD and NMR spectroscopy of synthetic transmembrane peptides; homology modeling based on ADP/ATP carrier crystal structure\",\n      \"journal\": \"The Italian journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 method (NMR structural characterization) but single lab, peptide fragments only, no mutagenesis functional validation\",\n      \"pmids\": [\"19192628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Germline loss-of-function mutations in SLC25A11 (encoding the mitochondrial 2-oxoglutarate/malate carrier) predispose to metastatic paraganglioma. Loss of SLC25A11 function (via CRISPR-Cas9 knockout in mouse chromaffin cells) produces pseudohypoxic and hypermethylator phenotypes comparable to those in SDHx- and FH-related tumors, indicating SLC25A11 acts as a tumor suppressor gene through disruption of mitochondrial metabolite transport.\",\n      \"method\": \"Whole-exome sequencing, loss of heterozygosity analysis, CRISPR-Cas9 knockout in mouse chromaffin cells with metabolic and epigenetic phenotyping\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with defined molecular phenotypes (pseudohypoxia, hypermethylation), replicated across seven patients and cell model\",\n      \"pmids\": [\"29431636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLC25A11 transports cytosolic NADH into mitochondria in the form of malate (as part of the malate-aspartate shuttle), and cancer cells (NSCLC and melanoma) exhibit higher cytosolic-to-mitochondrial NADH ratios and higher SLC25A11 expression than normal cells. Knockdown of SLC25A11 impairs mitochondrial ATP production and inhibits cancer cell growth, while heterozygous Slc25a11 knockout mice suppress KRAS-driven lung tumor formation.\",\n      \"method\": \"siRNA knockdown with ATP/NADH measurement, metabolite profiling, in vivo KRAS lung tumor cross-breeding model with heterozygous Slc25a11 knockout mice\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined metabolic phenotype (ATP, NADH), in vivo genetic model, multiple cancer cell lines\",\n      \"pmids\": [\"30686754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neutrophil extracellular traps (NETs) decrease the stability and dimerization of SLC25A11, assessed by blue native PAGE, leading to depletion of mitochondrial glutathione (mitoGSH), which induces ferroptosis in smooth muscle cells and promotes abdominal aortic aneurysm formation. SLC25A11 functions as a mitochondrial glutathione transporter whose dimerization state controls mitoGSH levels.\",\n      \"method\": \"Blue native PAGE (SLC25A11 dimerization), western blotting/immunofluorescence, in vitro SMC ferroptosis assay, in vivo angiotensin II AAA mouse model with PAD4 KO, transmission electron microscopy\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical measurement of SLC25A11 dimerization, multiple in vitro and in vivo models with defined ferroptosis phenotype\",\n      \"pmids\": [\"38796028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"N-phenylmaleimide (KN612) inhibits SLC25A11 (the αKG/malate antiporter component of the malate-aspartate shuttle in GBM), reducing oxygen consumption rate, ATP levels, mitochondrial activity, and cell viability in glioblastoma tumorspheres, and decreasing stemness and invasion; in vivo orthotopic xenograft treatment reduced tumor size and prolonged survival.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition (KN612), oxygen consumption rate measurement, ATP assay, in vivo orthotopic xenograft mouse model, transcriptomic analysis\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD plus pharmacological inhibition with defined bioenergetic readouts and in vivo validation, single lab\",\n      \"pmids\": [\"40405188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD1 deubiquitinates and stabilizes SLC25A11 protein, thereby increasing mitochondrial ROS and apoptosis in nasopharyngeal carcinoma cells; loss of OTUD1-mediated SLC25A11 stabilization enhances radioresistance, and this axis is regulated upstream by TFAP2C methylation.\",\n      \"method\": \"Co-immunoprecipitation (OTUD1-SLC25A11 interaction), deubiquitination assay, siRNA knockdown/overexpression with ROS and apoptosis readouts, in vitro and in vivo radioresistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and deubiquitination assay establishing PTM (ubiquitination) regulation of SLC25A11, single lab\",\n      \"pmids\": [\"40664662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Chronic hypoxia increases N6-methyladenosine (m6A) modification on the SLC25A11 3'UTR via METTL3, with m6A-binding protein YTHDF2 binding to the SLC25A11 3'UTR, leading to decreased SLC25A11 expression and subsequent ferroptosis and mitochondrial dysfunction in cardiomyocytes. SLC25A11 overexpression inhibits chronic hypoxia-induced ferroptosis; the METTL3 inhibitor STM2457 reverses this by restoring SLC25A11 levels.\",\n      \"method\": \"m6A methylation assay (MeRIP), YTHDF2 RIP (RNA immunoprecipitation), SLC25A11 overexpression/shRNA in cardiomyocytes, cell viability/ferroptosis assays, hypoxic mouse model\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP establishing m6A reader-SLC25A11 mRNA interaction, genetic rescue experiments, in vivo model; single lab\",\n      \"pmids\": [\"41404734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGC (Slc25a11) silencing in RPE cells aggravates TGF-β2-induced epithelial-to-mesenchymal transition (EMT) via pSmad2/3 upregulation dependent on PI3K/AKT signaling, and reduces mitochondrial respiration and mitoGSH; conversely, OGC overexpression attenuates EMT, cell proliferation, and migration. In vivo, OGC+/− mice show significantly augmented subretinal fibrosis after laser photocoagulation.\",\n      \"method\": \"siRNA knockdown and overexpression of OGC in ARPE-19 cells, EMT marker measurement (α-SMA, fibronectin, collagen I, E-cadherin, Slug), mitochondrial bioenergetics assay, PI3K/AKT/Smad2/3 pathway analysis, OCT and immunostaining in OGC+/− mice\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with pathway placement (PI3K/AKT/Smad), in vivo heterozygous mouse model; single lab\",\n      \"pmids\": [\"41147690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A11 inhibition leads to accumulation of TCA-related metabolites, loss of mitochondrial membrane potential, and mitochondrial lipid ROS accumulation. Loss of SLC25A11 reduces NRF2 expression/nuclear translocation and its interaction with ferroptosis suppressor FSP1, activating lipid peroxidation molecules ACSL4, LPCAT3, and PEBP1 to induce ferroptosis in biliary tract cancer cells.\",\n      \"method\": \"SLC25A11 knockdown/overexpression, RNA sequencing, mitochondrial membrane potential assay, lipid ROS imaging, NRF2-FSP1 co-immunoprecipitation, ACSL4/LPCAT3/PEBP1 protein expression, ferrostatin-1 rescue, in vivo tumor model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with RNA-seq pathway placement, Co-IP for NRF2-FSP1 interaction, ferrostatin-1 rescue; single lab\",\n      \"pmids\": [\"41514409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A11 (the mitochondrial αKG/malate antiporter) is required for KDM2A-dependent reduction of rRNA transcription: inhibition of SLC25A11 by N-phenylmaleimide or its knockdown blocks the AOA (aspartate transaminase inhibitor)-induced decrease in intracellular αKG, preventing KDM2A from demethylating H3K36me2 at the rRNA gene promoter. Supplementation with cell-permeable dimethyl-αKG restores KDM2A activity inhibited by SLC25A11 blockade, linking SLC25A11-mediated αKG export from mitochondria to epigenetic regulation of rRNA transcription.\",\n      \"method\": \"N-phenylmaleimide pharmacological inhibition of SLC25A11, siRNA knockdown of SLC25A11, intracellular ATP measurement, H3K36me2 ChIP at rRNA gene promoter, dimethyl-αKG supplementation rescue experiment in MCF-7 cells\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic inhibition with chromatin (ChIP) readout and metabolite rescue; single lab\",\n      \"pmids\": [\"41227300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A forward genetic screen using an αKG biosensor identified a sequential inter-organelle pathway in which GPT2 transaminase and SLC25A11 transporter together supply nuclear αKG required for chromatin demethylation; loss of this pathway in a mouse model of GPT2 deficiency alters chromatin methylation in the developing brain.\",\n      \"method\": \"αKG transcriptional biosensor (NtcA-based), CRISPR genetic screen, GPT2-deficient mouse model, chromatin methylation analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biosensor-coupled genetic screen with in vivo mouse model validation; preprint, single study\",\n      \"pmids\": [\"bio_10.1101_2025.04.06.647450\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SLC25A11 encodes the inner mitochondrial membrane 2-oxoglutarate/malate antiporter (OGC) that exchanges cytosolic malate for mitochondrial 2-oxoglutarate across six transmembrane α-helices; it functions as a core component of the malate-aspartate shuttle to transfer cytosolic NADH equivalents into mitochondria for ATP production, transports glutathione into the mitochondrial matrix (maintaining mitoGSH and preventing ferroptosis), and supplies nuclear α-ketoglutarate for chromatin demethylation, while its protein stability is regulated by OTUD1-mediated deubiquitination and METTL3-mediated m6A modification of its mRNA; loss-of-function activates pseudohypoxic/hypermethylator phenotypes and acts as a tumor suppressor in paraganglioma.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC25A11 is the inner mitochondrial membrane 2-oxoglutarate (α-ketoglutarate)/malate antiporter that operates as a core component of the malate-aspartate shuttle, transferring cytosolic NADH-reducing equivalents into the mitochondrial matrix to sustain oxidative phosphorylation and ATP production [PMID:30686754, PMID:40405188]. Beyond its canonical shuttle function, SLC25A11 transports glutathione into mitochondria to maintain the mitochondrial GSH pool, and its loss or destabilization triggers ferroptosis through lipid peroxidation and depleted antioxidant defense in multiple cell types [PMID:38796028, PMID:41404734, PMID:41514409]. SLC25A11 also supplies α-ketoglutarate to the nucleus via a GPT2–SLC25A11 inter-organelle relay, thereby fueling KDM2A-dependent histone H3K36me2 demethylation and controlling rRNA transcription and chromatin state [PMID:41227300]. Germline loss-of-function mutations in SLC25A11, combined with somatic loss of heterozygosity, cause pseudohypoxic and hypermethylator phenotypes that phenocopy SDHx/FH-mutant paragangliomas, establishing SLC25A11 as a tumor-suppressor gene [PMID:29431636].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Determining the secondary structure of OGC/SLC25A11 transmembrane segments established that all six helices adopt α-helical conformations consistent with the SLC25 family fold, providing the first structural framework for understanding its transport mechanism.\",\n      \"evidence\": \"CD and NMR spectroscopy on synthetic TMS peptides in membrane-mimetic environments, with homology modeling based on the ADP/ATP carrier crystal structure\",\n      \"pmids\": [\"19192628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only peptide fragments characterized, not full-length reconstituted protein\", \"No direct transport assay coupled to structural data\", \"No high-resolution structure of full-length SLC25A11\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that the C. elegans ortholog MISC-1/OGC physically interacts with anti-apoptotic CED-9/Bcl-xL and ANT, and that its loss induces caspase-dependent apoptosis and disrupts mitochondrial morphology, revealed that SLC25A11 functions beyond metabolite transport in apoptosis regulation and mitochondrial dynamics.\",\n      \"evidence\": \"Reciprocal pull-down assays, genetic epistasis in C. elegans, RNAi knockdown, transmission electron microscopy\",\n      \"pmids\": [\"21448454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction with Bcl-xL/ANT not confirmed in mammalian systems with endogenous proteins\", \"Whether apoptotic role is transport-dependent or scaffold-dependent is unresolved\", \"Mechanism linking OGC to mitochondrial fusion/fission machinery not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of germline SLC25A11 loss-of-function mutations in paraganglioma patients established SLC25A11 as a bona fide tumor-suppressor gene whose inactivation produces pseudohypoxic and hypermethylator phenotypes analogous to SDHx/FH deficiency, linking its metabolite transport function to oncogenesis.\",\n      \"evidence\": \"Whole-exome sequencing of patient tumors, CRISPR-Cas9 knockout in mouse chromaffin cells, loss-of-heterozygosity analysis, metabolomic and epigenomic profiling\",\n      \"pmids\": [\"29431636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Penetrance and spectrum of SLC25A11-mutant tumors not fully defined\", \"Whether pseudohypoxia arises from α-KG depletion, succinate/fumarate accumulation, or both is unclear\", \"No functional reconstitution of mutant transporter activity\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that SLC25A11 knockdown impairs mitochondrial ATP production and suppresses cancer cell growth while sparing normal cells — validated by in vivo tumor suppression in heterozygous knockout mice — established the malate-aspartate shuttle as a metabolic vulnerability in KRAS-driven lung cancer.\",\n      \"evidence\": \"siRNA knockdown with ATP/NADH measurement, metabolite profiling, heterozygous Slc25a11 knockout crossed with KRASLA2 lung cancer mouse model\",\n      \"pmids\": [\"30686754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity mechanism for cancer vs. normal cells not molecularly defined\", \"Contribution of SLC25A11 vs. other shuttle components not dissected\", \"No pharmacokinetic-grade inhibitor tested in vivo at this stage\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that neutrophil extracellular traps destabilize SLC25A11 dimers and deplete mitochondrial glutathione to induce smooth muscle cell ferroptosis linked SLC25A11's glutathione transport function to a specific vascular disease mechanism — abdominal aortic aneurysm.\",\n      \"evidence\": \"Blue native PAGE for dimerization, Western blotting, ferroptosis assays in smooth muscle cells, Padi4 knockout mouse model\",\n      \"pmids\": [\"38796028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct measurement of GSH transport rates through SLC25A11 dimers vs. monomers not performed\", \"Whether NET-mediated destabilization involves specific post-translational modifications is unknown\", \"Single disease model without independent replication\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple convergent studies established that SLC25A11 loss triggers ferroptosis across diverse cell types (cardiomyocytes, biliary tract cancer, RPE cells) through mitochondrial GSH depletion, lipid ROS accumulation, and disruption of NRF2/FSP1 and ACSL4/LPCAT3 pathways, while also revealing upstream regulatory control by METTL3/m6A-YTHDF2 (reducing expression) and OTUD1 deubiquitination (stabilizing protein).\",\n      \"evidence\": \"m6A-seq/MeRIP with METTL3 inhibitor rescue in cardiomyocytes; deubiquitination assays and radiosensitivity studies in NPC; RNA-seq, metabolomics, and NRF2 interaction analysis in biliary tract cancer; Seahorse respiration and mtGSH measurement with OGC+/- mouse subretinal fibrosis model\",\n      \"pmids\": [\"41404734\", \"40664662\", \"41514409\", \"41147690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ferroptosis is driven primarily by GSH depletion or by metabolic collapse from shuttle impairment remains unclear\", \"Relative contributions of transcriptional (m6A) vs. post-translational (ubiquitin) regulation in physiological contexts not compared\", \"No direct reconstitution of SLC25A11-dependent GSH transport kinetics\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pharmacological inhibition of SLC25A11 by N-phenylmaleimide validated the transporter as a druggable target in glioblastoma, reducing oxygen consumption and ATP levels and suppressing orthotopic tumor growth, confirming earlier genetic evidence of cancer cell dependence on the malate-aspartate shuttle.\",\n      \"evidence\": \"KN612/NPM pharmacological inhibition confirmed by SLC25A11 siRNA, Seahorse metabolic flux analysis, orthotopic xenograft model in glioblastoma\",\n      \"pmids\": [\"40405188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NPM is not specific to SLC25A11; off-target effects on other thiol-containing proteins not excluded\", \"No crystal structure of SLC25A11–inhibitor complex\", \"Long-term toxicity and therapeutic window not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing that SLC25A11 supplies nuclear α-ketoglutarate through a GPT2→SLC25A11 inter-organelle relay to fuel KDM2A-mediated H3K36me2 demethylation at rRNA promoters revealed a direct epigenetic function for mitochondrial metabolite export beyond bioenergetics.\",\n      \"evidence\": \"α-KG biosensor genetic screen, SLC25A11 siRNA and NPM inhibition with dimethyl-α-KG rescue, H3K36me2 ChIP, rRNA transcription quantification in MCF-7 cells\",\n      \"pmids\": [\"41227300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SLC25A11-derived α-KG fuels other α-KG-dependent dioxygenases (TETs, other KDMs) is untested\", \"Mechanism of α-KG transit from mitochondrial intermembrane space to nucleus not defined\", \"Quantitative contribution of SLC25A11 vs. IDH-derived cytosolic α-KG pools not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of SLC25A11, the molecular basis for its dual substrate specificity (α-KG/malate vs. GSH), the relative physiological importance of its bioenergetic versus epigenetic versus antioxidant functions in different tissues, and whether specific SLC25A11 inhibitors can be developed with acceptable therapeutic windows.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length human SLC25A11\", \"GSH transport kinetics and structural determinants not characterized\", \"Tissue-specific conditional knockout phenotypes not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 4, 8, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 6, 7, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 4, 8, 9, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 7, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 4, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BCL2L1\",\n      \"SLC25A4\",\n      \"OTUD1\",\n      \"KDM2A\",\n      \"GPT2\",\n      \"NRF2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SLC25A11 is the inner mitochondrial membrane 2-oxoglutarate/malate antiporter that operates as a core component of the malate-aspartate shuttle, transferring cytosolic NADH equivalents into mitochondria to sustain oxidative phosphorylation and ATP production [PMID:30686754, PMID:40405188]. Beyond this canonical bioenergetic role, SLC25A11 transports glutathione into the mitochondrial matrix, and disruption of its dimerization depletes mitochondrial GSH and triggers ferroptosis [PMID:38796028, PMID:41514409, PMID:41404734]. SLC25A11-mediated export of α-ketoglutarate from mitochondria supplies the cofactor required for KDM2A-dependent histone demethylation, linking mitochondrial metabolite exchange to epigenetic regulation, and germline loss-of-function mutations in SLC25A11 cause pseudohypoxic/hypermethylator phenotypes that predispose to metastatic paraganglioma [PMID:41227300, PMID:29431636]. Protein stability of SLC25A11 is controlled by OTUD1-mediated deubiquitination, while its mRNA abundance is regulated by METTL3/YTHDF2-dependent m6A modification [PMID:40664662, PMID:41404734].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Determining whether the OGC adopts the predicted six-transmembrane-helix architecture was essential for placing it within the mitochondrial carrier family; CD/NMR spectroscopy of all six transmembrane segments confirmed α-helical structures consistent with the ADP/ATP carrier fold.\",\n      \"evidence\": \"CD and NMR spectroscopy of synthetic OGC transmembrane peptides with homology modeling\",\n      \"pmids\": [\"19192628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structure determined\", \"No mutagenesis to test functional residues\", \"Peptide fragments studied in detergent/TFE rather than a lipid bilayer\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether SLC25A11 participates in processes beyond metabolite transport was unclear; interaction with anti-apoptotic CED-9/Bcl-xL and pro-apoptotic ANT, and genetic epistasis with the LIN-35/Rb pathway, established a role for OGC in mitochondrial morphology control and apoptosis induction.\",\n      \"evidence\": \"Pull-down assays, RNAi knockdown with apoptosis scoring, TEM, genetic epistasis in C. elegans and mammalian cells\",\n      \"pmids\": [\"21448454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the apoptotic role is conserved in all mammalian tissues remains unresolved\", \"No direct measurement of transport activity during apoptosis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The question of whether SLC25A11 loss could be oncogenic was answered when germline loss-of-function mutations were found in paraganglioma patients and CRISPR knockout reproduced pseudohypoxic and hypermethylator phenotypes, establishing SLC25A11 as a tumor suppressor gene analogous to SDHx/FH.\",\n      \"evidence\": \"Whole-exome sequencing of seven patients, LOH analysis, CRISPR-Cas9 knockout in mouse chromaffin cells with metabolic/epigenetic profiling\",\n      \"pmids\": [\"29431636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No rescue experiment restoring SLC25A11 in knockout cells\", \"Penetrance and spectrum of associated tumors not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How SLC25A11 supports tumor bioenergetics was clarified by showing that cancer cells rely on its malate-aspartate shuttle activity for mitochondrial NADH import and ATP production; knockdown impaired ATP synthesis, and heterozygous Slc25a11 knockout suppressed KRAS-driven lung tumorigenesis in vivo.\",\n      \"evidence\": \"siRNA knockdown with ATP/NADH measurement in NSCLC/melanoma lines, heterozygous Slc25a11 knockout crossed with KRAS-driven lung tumor model\",\n      \"pmids\": [\"30686754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other shuttle components compensate at different stoichiometries is unknown\", \"No direct flux measurement of malate/oxoglutarate exchange rates\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether SLC25A11 directly controls mitochondrial glutathione was uncertain; demonstration that NETs destabilize SLC25A11 dimers, deplete mitoGSH, and induce ferroptosis in smooth muscle cells established a non-canonical transport function—mitochondrial glutathione import—governed by SLC25A11 oligomeric state.\",\n      \"evidence\": \"Blue native PAGE (dimerization), mitoGSH quantification, ferroptosis assays in SMCs, angiotensin II AAA mouse model with PAD4 KO\",\n      \"pmids\": [\"38796028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct reconstitution of GSH transport by purified SLC25A11 not yet performed\", \"Structural basis of how dimerization controls GSH versus α-KG transport is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies converged on ferroptosis as a downstream consequence of SLC25A11 loss: m6A-mediated mRNA degradation by METTL3/YTHDF2 reduces SLC25A11 in hypoxic cardiomyocytes causing ferroptosis, and SLC25A11 depletion in biliary tract cancer activates ACSL4/LPCAT3/PEBP1 lipid peroxidation via NRF2-FSP1 axis collapse, consolidating ferroptosis as a central phenotype of SLC25A11 deficiency.\",\n      \"evidence\": \"MeRIP and RIP for m6A/YTHDF2-SLC25A11 mRNA interaction with genetic rescue in cardiomyocytes; NRF2-FSP1 Co-IP and ferrostatin-1 rescue in biliary tract cancer cells; in vivo models\",\n      \"pmids\": [\"41404734\", \"41514409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m6A regulation of SLC25A11 occurs in non-cardiac tissues is untested\", \"Relative contribution of GSH depletion versus α-KG imbalance to ferroptosis not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How SLC25A11 protein levels are maintained was answered by showing OTUD1 deubiquitinates SLC25A11, stabilizing it; loss of this axis increases radioresistance in nasopharyngeal carcinoma through reduced mitochondrial ROS and apoptosis.\",\n      \"evidence\": \"Co-IP and deubiquitination assay for OTUD1-SLC25A11, siRNA/overexpression with ROS and apoptosis readouts, in vivo radioresistance model\",\n      \"pmids\": [\"40664662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on SLC25A11 not mapped\", \"E3 ligase responsible for SLC25A11 ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The question of whether SLC25A11-exported α-ketoglutarate feeds nuclear epigenetic reactions was answered: SLC25A11 inhibition blocks α-KG-dependent KDM2A demethylation of H3K36me2 at rRNA gene promoters, and cell-permeable α-KG rescues the defect, establishing a mitochondria-to-nucleus metabolite signaling axis.\",\n      \"evidence\": \"N-phenylmaleimide inhibition and siRNA knockdown of SLC25A11, H3K36me2 ChIP at rRNA promoter, dimethyl-α-KG rescue in MCF-7 cells\",\n      \"pmids\": [\"41227300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this axis extends to other α-KG-dependent demethylases (e.g., TET enzymes) via SLC25A11 is untested\", \"Direct measurement of nuclear α-KG pools not performed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SLC25A11 haploinsufficiency aggravates EMT and subretinal fibrosis via PI3K/AKT/Smad2/3 signaling, extending the carrier's pathological relevance beyond cancer to fibrotic eye disease.\",\n      \"evidence\": \"siRNA/overexpression in RPE cells, EMT markers and pathway analysis, OGC+/− mice with laser-induced subretinal fibrosis\",\n      \"pmids\": [\"41147690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mitoGSH depletion or α-KG imbalance drives the EMT phenotype is not resolved\", \"Single tissue context (RPE cells)\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of SLC25A11 in a lipid membrane, direct reconstitution of GSH transport, identification of the E3 ubiquitin ligase counterpart to OTUD1, and whether the distinct transport cargoes (malate/α-KG versus GSH) use shared or distinct conformational mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution cryo-EM or crystal structure of SLC25A11\", \"No reconstituted proteoliposome assay distinguishing GSH from α-KG transport\", \"E3 ligase targeting SLC25A11 for ubiquitination unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [3, 4, 10, 11]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 5, 10]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 3, 4, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 4, 6, 7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 5, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"OTUD1\",\n      \"YTHDF2\",\n      \"GPT2\",\n      \"BCL2L1\",\n      \"ANT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}