{"gene":"SLC25A10","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2005,"finding":"SLC25A10 (Slc25a10) transports malate across the mitochondrial inner membrane to supply malate for citrate export during de novo fatty acid synthesis. siRNA-mediated knockdown of Slc25a10 in HepG2 and 3T3-L1 cells significantly reduced citrate transport from mitochondria to cytosol, decreased ACC1 expression and malonyl-CoA levels, and reduced triglyceride accumulation in differentiated adipocytes.","method":"siRNA knockdown in HepG2 and 3T3-L1 cell lines; measurement of citrate transport, ACC1 expression, malonyl-CoA levels, and triglyceride accumulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined metabolic phenotype, multiple orthogonal readouts, single lab","pmids":["16027120"],"is_preprint":false},{"year":2015,"finding":"SLC25A10 knockdown in A549 lung cancer cells shifted energy metabolism from glycolysis toward mitochondrial oxidative phosphorylation, increased glutamine dependency, increased sensitivity to oxidative stress, decreased NADPH production under glutamine deprivation, and reduced malignant growth properties. These effects were linked to decreased HIF-1α and lactate dehydrogenase expression and increased glutamate dehydrogenase expression.","method":"siRNA knockdown in A549 cells; measurement of cell growth, ROS levels, NADPH production, gene expression (HIF-1α, LDH, GDH), oxygen consumption, and metabolic parameters","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple metabolic phenotype readouts, single lab, multiple orthogonal methods","pmids":["25797253"],"is_preprint":false},{"year":2018,"finding":"Biallelic loss-of-function mutations in SLC25A10 in a patient caused absence of SLC25A10 protein and loss of its transporting function, associated with respiratory complex I deficiency, mitochondrial DNA depletion, and severe epileptic encephalopathy. The yeast SLC25A10 ortholog knockout showed defects in mitochondrial respiration and mitochondrial DNA content. Transport assays demonstrated that SLC25A10 is unable to transport glutathione despite patient fibroblasts being depleted in NADPH and glutathione.","method":"Whole exome sequencing; patient fibroblast functional analysis; yeast ortholog knockout; transport assays; RNA and protein quantification","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — human genetic disease validation combined with transport assays, yeast KO replication, and multiple orthogonal methods across patient and model organism systems","pmids":["29211846"],"is_preprint":false},{"year":2019,"finding":"The circadian clock protein CLOCK directly binds SLC25A10 protein. Amino acids 43–84 and 169–210 in SLC25A10 are key sites mediating CLOCK binding. Loss of SLC25A10 (CRISPR/Cas9 knockout in Hepa1-6 cells) caused disordered glucose homeostasis, increased oxidative stress, and damaged electron transport chain function. Rescue with wild-type SLC25A10 restored these defects, while a mutant lacking the CLOCK-binding sites failed to rescue, establishing these sites as functionally required.","method":"Co-immunoprecipitation; CRISPR/Cas9 knockout cell line generation; rescue with wild-type vs. mutant SLC25A10; measurement of glucose metabolism, ROS, and electron transport chain function","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP binding identification plus KO/rescue with mutagenesis, single lab","pmids":["30943427"],"is_preprint":false},{"year":2001,"finding":"Import of the dicarboxylate carrier (DIC/SLC25A10) into mitochondria follows a distinct pathway from the ADP/ATP carrier (AAC): DIC shows complete membrane potential (ΔΨ)-independent translocation across the outer mitochondrial membrane and release from the import pore, accumulating in a soluble state in the intermembrane space (stage III*). This defines a new translocation intermediate distinct from other mitochondrial carriers.","method":"In vitro mitochondrial import assays using yeast Saccharomyces cerevisiae mitochondria; comparison with AAC import pathway; membrane potential manipulation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro import assay with mechanistic dissection of import stages, direct comparison to established carrier pathway","pmids":["11502005"],"is_preprint":false},{"year":2009,"finding":"Over-expression of DIC-1 (C. elegans ortholog of SLC25A10) greatly increased the number and fractional area of mitochondrial cristae, increased oxygen consumption rate and ATP content, and decreased reactive oxygen species and paraquat sensitivity. Conversely, DIC-1 knockdown induced opposite changes in ATP, ROS, and paraquat sensitivity, demonstrating that DIC-1 actively participates in cristae formation and thereby regulates oxidative phosphorylation.","method":"Transient over-expression in C. elegans; cryo-electron microscopy of mitochondrial morphology; measurement of oxygen consumption, ATP content, ROS levels, and paraquat sensitivity; RNAi knockdown","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cryo-EM structural observation plus functional metabolic readouts with both OE and KD, single lab, C. elegans ortholog","pmids":["19210547"],"is_preprint":false},{"year":2018,"finding":"Metformin treatment decreased SLC25A10 gene and protein expression in A549 lung cancer cells, with the effect more pronounced at low glucose concentrations. In SLC25A10 knockdown cells, metformin significantly further reduced SLC25A10 at both mRNA and protein levels and markedly increased expression of the cyclin-dependent kinase inhibitor CDKN1A (p21), suggesting that metformin can affect nutrient supply and metabolic state of cancer cells through SLC25A10.","method":"siRNA knockdown; metformin treatment; qRT-PCR and western blot for SLC25A10 and metabolic gene expression; growth at varying glucose concentrations","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gene/protein expression changes with pharmacological treatment, single lab, no direct transport or mechanistic assay","pmids":["30222970"],"is_preprint":false},{"year":2017,"finding":"siRNA knockdown of SLC25A10 in in vitro differentiated human adipocytes inhibited insulin-stimulated lipogenesis under conditions where glucose transport is the rate-limiting step. Transcriptome profiling of siRNA-treated cells showed only modest transcriptional changes, suggesting SLC25A10 directly influences insulin sensitivity in adipocytes through its transport function rather than transcriptional regulation.","method":"siRNA knockdown in differentiated human adipocytes; measurement of insulin-stimulated lipogenesis; microarray transcriptome profiling","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional lipogenesis assay plus transcriptome profiling, single lab, two orthogonal methods","pmids":["28570579"],"is_preprint":false},{"year":2022,"finding":"PYCR1 promoted SLC25A10 expression in colorectal cancer cells. SLC25A10 overexpression reversed the antitumor effects of PYCR1 silencing in vitro, including restoration of lipid ROS suppression and inhibition of ferroptosis. In vivo, SLC25A10 overexpression inhibited the antitumor effects of the ferroptosis inducer erastin, establishing SLC25A10 as a downstream effector of PYCR1 in suppressing ferroptosis.","method":"siRNA knockdown and overexpression in colorectal cancer cells; lipid ROS measurement; ferroptosis inhibitor/inducer experiments (deferoxamine, erastin); in vivo tumor models","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue/overexpression experiments with multiple ferroptosis readouts, single lab","pmids":["36104652"],"is_preprint":false},{"year":2020,"finding":"SLC25A10 knockdown in osteosarcoma cells significantly suppressed cell proliferation, increased apoptosis, and decreased mitosis. SLC25A10 positively regulated CCNE1 (Cyclin E1) expression while negatively regulating P21 and P27, suggesting SLC25A10 promotes osteosarcoma cell growth through regulation of cell cycle proteins.","method":"shRNA knockdown; cell counting, MTT assay, colony formation assay; flow cytometry for apoptosis and mitosis; western blot for CCNE1, P21, P27","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single KD approach with phenotypic readouts and protein expression changes, single lab, no direct mechanistic link established","pmids":["32774476"],"is_preprint":false},{"year":2024,"finding":"MPV17 maintains the protein homeostasis of SLC25A10 by preventing its ubiquitination-dependent degradation during iron overload conditions. MPV17 absence in iron overload resulted in degradation of SLC25A10, impairing mitochondrial glutathione import. SLC25A10 functions as a mitochondrial inner-membrane glutathione transporter, and the Nrf2-MPV17-SLC25A10/mitochondrial glutathione axis regulates myocardial ferroptosis.","method":"Adenovirus-mediated MPV17 overexpression; SLC25A10 protein stability assay; ubiquitination assay; mitochondrial glutathione measurement; cardiomyocyte iron overload and I/R models","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway placement with ubiquitination and transport functional data, single lab, multiple complementary methods","pmids":["39409161"],"is_preprint":false},{"year":2024,"finding":"SLC25A10 expression was suppressed in ischemia/reperfusion (I/R) rat myocardium and in hypoxia/reoxygenation (H/R) cardiomyocytes. Mild therapeutic hypothermia (MTH) reversed this suppression. SLC25A10 deletion partially reversed the protective effects of MTH on H/R cardiomyocytes, including reversal of the inhibition of the mitochondrial apoptosis pathway, establishing SLC25A10 as a mediator of MTH cardioprotection against I/R injury.","method":"Proteomics identification; siRNA/gene deletion of SLC25A10; measurement of cell injury markers, mitochondrial dysfunction, and mitochondrial apoptosis pathway activation in H/R cardiomyocytes and I/R rat model","journal":"Journal of cardiovascular translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomics-identified target with partial genetic validation, single lab, no direct transport assay","pmids":["38568407"],"is_preprint":false}],"current_model":"SLC25A10 (dicarboxylate carrier, DIC) is a mitochondrial inner membrane transporter that exchanges dicarboxylates (malate, succinate) for phosphate/sulfate across the inner mitochondrial membrane; it supplies malate for citrate export required for de novo fatty acid synthesis, regulates NADPH production and redox balance (including mitochondrial glutathione import), influences oxidative phosphorylation and cristae formation, and its biogenesis involves a membrane-potential-independent translocation pathway through the mitochondrial intermembrane space distinct from other carrier proteins; loss-of-function causes mitochondrial respiratory defects and is linked to severe epileptic encephalopathy in humans, while its overexpression in cancer cells promotes metabolic reprogramming and ferroptosis resistance through interaction with CLOCK and downstream regulation of PYCR1/lipid ROS pathways."},"narrative":{"mechanistic_narrative":"SLC25A10 (the dicarboxylate carrier, DIC) is a mitochondrial inner-membrane transporter that moves dicarboxylates such as malate across the membrane to supply citrate export for de novo fatty acid synthesis, linking it to lipogenesis, redox homeostasis, and oxidative phosphorylation [PMID:16027120]. Its transport activity feeds NADPH production and cellular redox balance: knockdown shifts metabolism away from glycolysis toward mitochondrial respiration, raises sensitivity to oxidative stress, and lowers NADPH under glutamine deprivation [PMID:25797253], and in differentiated adipocytes the carrier supports insulin-stimulated lipogenesis through its transport function rather than transcriptional regulation [PMID:28570579]. At the organellar level the carrier promotes mitochondrial cristae formation and thereby tunes oxygen consumption, ATP content, and ROS levels [PMID:19210547]. Biallelic loss-of-function mutations in SLC25A10 cause loss of the protein and its transport activity, complex I deficiency, mitochondrial DNA depletion, and severe epileptic encephalopathy, with transport assays showing the carrier does not transport glutathione [PMID:29211846]. Biogenesis of the carrier proceeds by a membrane-potential-independent translocation pathway that accumulates a soluble intermembrane-space intermediate distinct from the ADP/ATP carrier import route [PMID:11502005]. The protein is bound directly by the circadian clock protein CLOCK through defined sites required for its support of glucose homeostasis, redox balance, and electron transport chain function [PMID:30943427], and it is stabilized against ubiquitination-dependent degradation by MPV17 within an Nrf2–MPV17–SLC25A10 axis governing mitochondrial glutathione handling and ferroptosis [PMID:39409161]. In cancer contexts SLC25A10 acts downstream of PYCR1 to suppress lipid ROS and ferroptosis [PMID:36104652].","teleology":[{"year":2001,"claim":"Established how the dicarboxylate carrier is delivered to mitochondria, defining a biogenesis route distinct from canonical carrier import.","evidence":"In vitro import assays in yeast mitochondria with membrane-potential manipulation, compared against the ADP/ATP carrier","pmids":["11502005"],"confidence":"High","gaps":["Does not identify the protein machinery handling the soluble intermembrane-space intermediate","Performed in yeast; human-specific import determinants not addressed"]},{"year":2005,"claim":"Connected SLC25A10 transport activity to a metabolic output, showing it supplies malate for citrate export feeding de novo fatty acid synthesis.","evidence":"siRNA knockdown in HepG2 and 3T3-L1 cells with citrate transport, ACC1, malonyl-CoA, and triglyceride readouts","pmids":["16027120"],"confidence":"Medium","gaps":["Substrate selectivity not directly measured in this system","Single lab; in vitro cell models only"]},{"year":2009,"claim":"Demonstrated an organellar structural role, linking carrier abundance to cristae formation and the efficiency of oxidative phosphorylation.","evidence":"Overexpression and RNAi of the C. elegans ortholog DIC-1 with cryo-EM cristae morphometry plus ATP, ROS, and paraquat-sensitivity assays","pmids":["19210547"],"confidence":"Medium","gaps":["Mechanism linking dicarboxylate transport to cristae remodeling unknown","Ortholog-based; human relevance inferred"]},{"year":2015,"claim":"Placed SLC25A10 in redox and metabolic reprogramming, showing its loss forces oxidative metabolism and impairs NADPH-dependent stress defense in cancer cells.","evidence":"siRNA knockdown in A549 cells with metabolic flux, NADPH, ROS, oxygen consumption, and gene-expression readouts","pmids":["25797253"],"confidence":"Medium","gaps":["Causal link between transport flux and HIF-1α/LDH/GDH changes not resolved","Single cell line"]},{"year":2017,"claim":"Distinguished transport function from transcriptional effects, showing the carrier supports adipocyte insulin-stimulated lipogenesis directly.","evidence":"siRNA knockdown in differentiated human adipocytes with lipogenesis assay and microarray transcriptome profiling","pmids":["28570579"],"confidence":"Medium","gaps":["Does not define which transported metabolite mediates the insulin effect","Single lab"]},{"year":2018,"claim":"Provided human genetic proof of essentiality, tying loss of the carrier to mitochondrial respiratory failure and disease, and excluding glutathione as a substrate at that point.","evidence":"Whole-exome sequencing of a patient, fibroblast functional analysis, yeast ortholog knockout, and transport assays","pmids":["29211846"],"confidence":"High","gaps":["Mechanism linking transport loss to mtDNA depletion and complex I deficiency unresolved","Single patient"]},{"year":2018,"claim":"Tested pharmacological modulation, linking metformin action on cancer metabolism to suppression of SLC25A10 expression.","evidence":"siRNA knockdown plus metformin treatment in A549 cells with qRT-PCR, western blot, and CDKN1A readouts","pmids":["30222970"],"confidence":"Low","gaps":["Expression-only correlation; no direct transport or mechanistic assay","Causality between metformin and SLC25A10 not established"]},{"year":2019,"claim":"Identified a direct protein partner, showing CLOCK binds defined SLC25A10 sites that are functionally required for glucose homeostasis and ETC support.","evidence":"Reciprocal Co-IP, CRISPR/Cas9 knockout, and rescue with wild-type versus CLOCK-binding-site mutant in Hepa1-6 cells","pmids":["30943427"],"confidence":"Medium","gaps":["Functional consequence of the CLOCK–SLC25A10 interaction at the molecular level unclear","No structural model of the interaction"]},{"year":2020,"claim":"Linked SLC25A10 to proliferative control in tumor cells via cell-cycle protein regulation.","evidence":"shRNA knockdown in osteosarcoma cells with proliferation, apoptosis, mitosis, and CCNE1/P21/P27 readouts","pmids":["32774476"],"confidence":"Low","gaps":["No direct mechanistic link between transport activity and cell-cycle protein regulation","Single knockdown approach"]},{"year":2022,"claim":"Positioned SLC25A10 as a ferroptosis-suppressing effector downstream of PYCR1 in cancer.","evidence":"Knockdown/overexpression epistasis in colorectal cancer cells with lipid ROS, ferroptosis inducer/inhibitor experiments, and in vivo tumor models","pmids":["36104652"],"confidence":"Medium","gaps":["Molecular mechanism by which PYCR1 controls SLC25A10 expression unknown","Transported substrate mediating ferroptosis resistance not identified"]},{"year":2024,"claim":"Defined a stability-control axis and assigned a glutathione-transport role, showing MPV17 protects SLC25A10 from ubiquitination-dependent degradation to maintain mitochondrial glutathione import.","evidence":"MPV17 overexpression, protein stability and ubiquitination assays, and mitochondrial glutathione measurement in cardiomyocyte iron-overload and I/R models","pmids":["39409161"],"confidence":"Medium","gaps":["Glutathione-transport assignment conflicts with earlier transport assays excluding glutathione (#2)","E3 ligase mediating degradation not identified"]},{"year":2024,"claim":"Implicated SLC25A10 as a mediator of cardioprotection, showing its expression is suppressed in I/R injury and restored by mild therapeutic hypothermia.","evidence":"Proteomics, siRNA/gene deletion, and mitochondrial apoptosis pathway readouts in H/R cardiomyocytes and I/R rat model","pmids":["38568407"],"confidence":"Low","gaps":["Proteomics-identified target with only partial genetic validation","No direct transport assay linking carrier function to protection"]},{"year":null,"claim":"The substrate spectrum of SLC25A10 remains unsettled, with transport assays excluding glutathione yet a glutathione-import role asserted via the MPV17 axis.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Definitive reconstituted determination of physiological substrates (malate, succinate, phosphate, sulfate, glutathione) is unresolved","Mechanism connecting transport flux to cristae formation and mtDNA maintenance unknown","Structural basis of CLOCK and MPV17 interactions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,10]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,4,5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,10]}],"complexes":[],"partners":["CLOCK","MPV17","PYCR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBX3","full_name":"Mitochondrial dicarboxylate carrier","aliases":["Solute carrier family 25 member 10"],"length_aa":287,"mass_kda":31.3,"function":"Catalyzes the electroneutral exchange or flux of physiologically important metabolites such as dicarboxylates (malonate, malate, succinate), inorganic sulfur-containing anions, and phosphate, across the mitochondrial inner membrane (PubMed:29211846, PubMed:38780415, PubMed:38937634). 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 (By similarity). Plays an important role in gluconeogenesis, fatty acid metabolism, urea synthesis, and sulfur metabolism, particularly in liver, by supplying the substrates for the different metabolic processes. Regulates fatty acid release from adipocytes, and contributes to systemic insulin sensitivity (By similarity)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9UBX3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC25A10","classification":"Not Classified","n_dependent_lines":232,"n_total_lines":1208,"dependency_fraction":0.19205298013245034},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC25A10","total_profiled":1310},"omim":[{"mim_id":"618972","title":"MITOCHONDRIAL DNA DEPLETION SYNDROME 19; MTDPS19","url":"https://www.omim.org/entry/618972"},{"mim_id":"609737","title":"CRUMBS CELL POLARITY COMPLEX COMPONENT 3; CRB3","url":"https://www.omim.org/entry/609737"},{"mim_id":"606794","title":"SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER), MEMBER 10; 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suecica.","date":"2021","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33459952","citation_count":8,"is_preprint":false},{"pmid":"12774341","id":"PMC_12774341","title":"Role of DIC in multiple organ failure.","date":"2000","source":"International journal of surgical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/12774341","citation_count":8,"is_preprint":false},{"pmid":"8897764","id":"PMC_8897764","title":"Swift transformation and locomotion of polymorphonuclear leukocytes and microglia as observed by VEC-DIC microscopy (video microscopy).","date":"1996","source":"The Keio journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8897764","citation_count":8,"is_preprint":false},{"pmid":"19231818","id":"PMC_19231818","title":"Characterization of the cationic DiC(14)-amidine bilayer by mixed DMPC/DiC(14)-amidine molecular dynamics simulations shows an interdigitated nonlamellar bilayer phase.","date":"2009","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/19231818","citation_count":8,"is_preprint":false},{"pmid":"38066933","id":"PMC_38066933","title":"Labor and delivery: DIC, HELLP, preeclampsia.","date":"2023","source":"Hematology. 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Education Program","url":"https://pubmed.ncbi.nlm.nih.gov/38066933","citation_count":7,"is_preprint":false},{"pmid":"39409161","id":"PMC_39409161","title":"MPV17 Prevents Myocardial Ferroptosis and Ischemic Cardiac Injury through Maintaining SLC25A10-Mediated Mitochondrial Glutathione Import.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39409161","citation_count":7,"is_preprint":false},{"pmid":"38568407","id":"PMC_38568407","title":"Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis.","date":"2024","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/38568407","citation_count":7,"is_preprint":false},{"pmid":"22728069","id":"PMC_22728069","title":"A novel fibrinogenase from Agkistrodon acutus venom protects against DIC via direct degradation of thrombosis and activation of protein C.","date":"2012","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22728069","citation_count":7,"is_preprint":false},{"pmid":"31149379","id":"PMC_31149379","title":"Lung cancer diagnosis with quantitative DIC microscopy and a deep convolutional neural network.","date":"2019","source":"Biomedical optics express","url":"https://pubmed.ncbi.nlm.nih.gov/31149379","citation_count":7,"is_preprint":false},{"pmid":"25426168","id":"PMC_25426168","title":"Delineation variable genotype/phenotype correlations of 6q27 terminal deletion derived from dic(6;18)(q27;p10).","date":"2014","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25426168","citation_count":7,"is_preprint":false},{"pmid":"15961230","id":"PMC_15961230","title":"Phase contrast and DIC illumination for AFM hybrids.","date":"2005","source":"Ultramicroscopy","url":"https://pubmed.ncbi.nlm.nih.gov/15961230","citation_count":7,"is_preprint":false},{"pmid":"3768966","id":"PMC_3768966","title":"Video microscopy of colloidal gold particles and immuno-gold labelled microtubules in improved rectified DIC and epi-illumination.","date":"1986","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/3768966","citation_count":7,"is_preprint":false},{"pmid":"7896498","id":"PMC_7896498","title":"N-cyclohexyl-N'-isopropylcarbodiimide: a hybrid that combines the structural features of DCC and DIC.","date":"1994","source":"International journal of peptide and protein research","url":"https://pubmed.ncbi.nlm.nih.gov/7896498","citation_count":7,"is_preprint":false},{"pmid":"3867118","id":"PMC_3867118","title":"Analyses of factor XII, prekallikrein and kallikrein inhibitory capacity in patients with laboratory signs of DIC.","date":"1985","source":"Scandinavian journal of clinical and laboratory investigation. Supplementum","url":"https://pubmed.ncbi.nlm.nih.gov/3867118","citation_count":7,"is_preprint":false},{"pmid":"39019125","id":"PMC_39019125","title":"Synthetic antimicrobial Nkl and Dic peptides are immunomodulatory but only Dic peptide can be therapeutic against nodavirus infection.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39019125","citation_count":6,"is_preprint":false},{"pmid":"26414653","id":"PMC_26414653","title":"Perioperative blood loss and gastrointestinal tolerability of etoricoxib and diclofenac in total hip arthroplasty (ETO-DIC study): a single-center, prospective double-blinded randomized controlled trial.","date":"2015","source":"Current medical research and opinion","url":"https://pubmed.ncbi.nlm.nih.gov/26414653","citation_count":6,"is_preprint":false},{"pmid":"16974089","id":"PMC_16974089","title":"A family case of fertile human 45,X,psu dic(15;Y) males.","date":"2006","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16974089","citation_count":6,"is_preprint":false},{"pmid":"35130927","id":"PMC_35130927","title":"An evaluation of circulating activated TAFI in septic DIC: a case series and review of the literature.","date":"2022","source":"Thrombosis journal","url":"https://pubmed.ncbi.nlm.nih.gov/35130927","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47550,"output_tokens":3435,"usd":0.097087,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11216,"output_tokens":3742,"usd":0.074815,"stage2_stop_reason":"end_turn"},"total_usd":0.171902,"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\": \"SLC25A10 (Slc25a10) transports malate across the mitochondrial inner membrane to supply malate for citrate export during de novo fatty acid synthesis. siRNA-mediated knockdown of Slc25a10 in HepG2 and 3T3-L1 cells significantly reduced citrate transport from mitochondria to cytosol, decreased ACC1 expression and malonyl-CoA levels, and reduced triglyceride accumulation in differentiated adipocytes.\",\n      \"method\": \"siRNA knockdown in HepG2 and 3T3-L1 cell lines; measurement of citrate transport, ACC1 expression, malonyl-CoA levels, and triglyceride accumulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined metabolic phenotype, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"16027120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC25A10 knockdown in A549 lung cancer cells shifted energy metabolism from glycolysis toward mitochondrial oxidative phosphorylation, increased glutamine dependency, increased sensitivity to oxidative stress, decreased NADPH production under glutamine deprivation, and reduced malignant growth properties. These effects were linked to decreased HIF-1α and lactate dehydrogenase expression and increased glutamate dehydrogenase expression.\",\n      \"method\": \"siRNA knockdown in A549 cells; measurement of cell growth, ROS levels, NADPH production, gene expression (HIF-1α, LDH, GDH), oxygen consumption, and metabolic parameters\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple metabolic phenotype readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25797253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biallelic loss-of-function mutations in SLC25A10 in a patient caused absence of SLC25A10 protein and loss of its transporting function, associated with respiratory complex I deficiency, mitochondrial DNA depletion, and severe epileptic encephalopathy. The yeast SLC25A10 ortholog knockout showed defects in mitochondrial respiration and mitochondrial DNA content. Transport assays demonstrated that SLC25A10 is unable to transport glutathione despite patient fibroblasts being depleted in NADPH and glutathione.\",\n      \"method\": \"Whole exome sequencing; patient fibroblast functional analysis; yeast ortholog knockout; transport assays; RNA and protein quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — human genetic disease validation combined with transport assays, yeast KO replication, and multiple orthogonal methods across patient and model organism systems\",\n      \"pmids\": [\"29211846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The circadian clock protein CLOCK directly binds SLC25A10 protein. Amino acids 43–84 and 169–210 in SLC25A10 are key sites mediating CLOCK binding. Loss of SLC25A10 (CRISPR/Cas9 knockout in Hepa1-6 cells) caused disordered glucose homeostasis, increased oxidative stress, and damaged electron transport chain function. Rescue with wild-type SLC25A10 restored these defects, while a mutant lacking the CLOCK-binding sites failed to rescue, establishing these sites as functionally required.\",\n      \"method\": \"Co-immunoprecipitation; CRISPR/Cas9 knockout cell line generation; rescue with wild-type vs. mutant SLC25A10; measurement of glucose metabolism, ROS, and electron transport chain function\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP binding identification plus KO/rescue with mutagenesis, single lab\",\n      \"pmids\": [\"30943427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Import of the dicarboxylate carrier (DIC/SLC25A10) into mitochondria follows a distinct pathway from the ADP/ATP carrier (AAC): DIC shows complete membrane potential (ΔΨ)-independent translocation across the outer mitochondrial membrane and release from the import pore, accumulating in a soluble state in the intermembrane space (stage III*). This defines a new translocation intermediate distinct from other mitochondrial carriers.\",\n      \"method\": \"In vitro mitochondrial import assays using yeast Saccharomyces cerevisiae mitochondria; comparison with AAC import pathway; membrane potential manipulation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro import assay with mechanistic dissection of import stages, direct comparison to established carrier pathway\",\n      \"pmids\": [\"11502005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Over-expression of DIC-1 (C. elegans ortholog of SLC25A10) greatly increased the number and fractional area of mitochondrial cristae, increased oxygen consumption rate and ATP content, and decreased reactive oxygen species and paraquat sensitivity. Conversely, DIC-1 knockdown induced opposite changes in ATP, ROS, and paraquat sensitivity, demonstrating that DIC-1 actively participates in cristae formation and thereby regulates oxidative phosphorylation.\",\n      \"method\": \"Transient over-expression in C. elegans; cryo-electron microscopy of mitochondrial morphology; measurement of oxygen consumption, ATP content, ROS levels, and paraquat sensitivity; RNAi knockdown\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cryo-EM structural observation plus functional metabolic readouts with both OE and KD, single lab, C. elegans ortholog\",\n      \"pmids\": [\"19210547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Metformin treatment decreased SLC25A10 gene and protein expression in A549 lung cancer cells, with the effect more pronounced at low glucose concentrations. In SLC25A10 knockdown cells, metformin significantly further reduced SLC25A10 at both mRNA and protein levels and markedly increased expression of the cyclin-dependent kinase inhibitor CDKN1A (p21), suggesting that metformin can affect nutrient supply and metabolic state of cancer cells through SLC25A10.\",\n      \"method\": \"siRNA knockdown; metformin treatment; qRT-PCR and western blot for SLC25A10 and metabolic gene expression; growth at varying glucose concentrations\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gene/protein expression changes with pharmacological treatment, single lab, no direct transport or mechanistic assay\",\n      \"pmids\": [\"30222970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA knockdown of SLC25A10 in in vitro differentiated human adipocytes inhibited insulin-stimulated lipogenesis under conditions where glucose transport is the rate-limiting step. Transcriptome profiling of siRNA-treated cells showed only modest transcriptional changes, suggesting SLC25A10 directly influences insulin sensitivity in adipocytes through its transport function rather than transcriptional regulation.\",\n      \"method\": \"siRNA knockdown in differentiated human adipocytes; measurement of insulin-stimulated lipogenesis; microarray transcriptome profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional lipogenesis assay plus transcriptome profiling, single lab, two orthogonal methods\",\n      \"pmids\": [\"28570579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PYCR1 promoted SLC25A10 expression in colorectal cancer cells. SLC25A10 overexpression reversed the antitumor effects of PYCR1 silencing in vitro, including restoration of lipid ROS suppression and inhibition of ferroptosis. In vivo, SLC25A10 overexpression inhibited the antitumor effects of the ferroptosis inducer erastin, establishing SLC25A10 as a downstream effector of PYCR1 in suppressing ferroptosis.\",\n      \"method\": \"siRNA knockdown and overexpression in colorectal cancer cells; lipid ROS measurement; ferroptosis inhibitor/inducer experiments (deferoxamine, erastin); in vivo tumor models\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue/overexpression experiments with multiple ferroptosis readouts, single lab\",\n      \"pmids\": [\"36104652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SLC25A10 knockdown in osteosarcoma cells significantly suppressed cell proliferation, increased apoptosis, and decreased mitosis. SLC25A10 positively regulated CCNE1 (Cyclin E1) expression while negatively regulating P21 and P27, suggesting SLC25A10 promotes osteosarcoma cell growth through regulation of cell cycle proteins.\",\n      \"method\": \"shRNA knockdown; cell counting, MTT assay, colony formation assay; flow cytometry for apoptosis and mitosis; western blot for CCNE1, P21, P27\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single KD approach with phenotypic readouts and protein expression changes, single lab, no direct mechanistic link established\",\n      \"pmids\": [\"32774476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MPV17 maintains the protein homeostasis of SLC25A10 by preventing its ubiquitination-dependent degradation during iron overload conditions. MPV17 absence in iron overload resulted in degradation of SLC25A10, impairing mitochondrial glutathione import. SLC25A10 functions as a mitochondrial inner-membrane glutathione transporter, and the Nrf2-MPV17-SLC25A10/mitochondrial glutathione axis regulates myocardial ferroptosis.\",\n      \"method\": \"Adenovirus-mediated MPV17 overexpression; SLC25A10 protein stability assay; ubiquitination assay; mitochondrial glutathione measurement; cardiomyocyte iron overload and I/R models\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway placement with ubiquitination and transport functional data, single lab, multiple complementary methods\",\n      \"pmids\": [\"39409161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC25A10 expression was suppressed in ischemia/reperfusion (I/R) rat myocardium and in hypoxia/reoxygenation (H/R) cardiomyocytes. Mild therapeutic hypothermia (MTH) reversed this suppression. SLC25A10 deletion partially reversed the protective effects of MTH on H/R cardiomyocytes, including reversal of the inhibition of the mitochondrial apoptosis pathway, establishing SLC25A10 as a mediator of MTH cardioprotection against I/R injury.\",\n      \"method\": \"Proteomics identification; siRNA/gene deletion of SLC25A10; measurement of cell injury markers, mitochondrial dysfunction, and mitochondrial apoptosis pathway activation in H/R cardiomyocytes and I/R rat model\",\n      \"journal\": \"Journal of cardiovascular translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomics-identified target with partial genetic validation, single lab, no direct transport assay\",\n      \"pmids\": [\"38568407\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A10 (dicarboxylate carrier, DIC) is a mitochondrial inner membrane transporter that exchanges dicarboxylates (malate, succinate) for phosphate/sulfate across the inner mitochondrial membrane; it supplies malate for citrate export required for de novo fatty acid synthesis, regulates NADPH production and redox balance (including mitochondrial glutathione import), influences oxidative phosphorylation and cristae formation, and its biogenesis involves a membrane-potential-independent translocation pathway through the mitochondrial intermembrane space distinct from other carrier proteins; loss-of-function causes mitochondrial respiratory defects and is linked to severe epileptic encephalopathy in humans, while its overexpression in cancer cells promotes metabolic reprogramming and ferroptosis resistance through interaction with CLOCK and downstream regulation of PYCR1/lipid ROS pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC25A10 (the dicarboxylate carrier, DIC) is a mitochondrial inner-membrane transporter that moves dicarboxylates such as malate across the membrane to supply citrate export for de novo fatty acid synthesis, linking it to lipogenesis, redox homeostasis, and oxidative phosphorylation [#0]. Its transport activity feeds NADPH production and cellular redox balance: knockdown shifts metabolism away from glycolysis toward mitochondrial respiration, raises sensitivity to oxidative stress, and lowers NADPH under glutamine deprivation [#1], and in differentiated adipocytes the carrier supports insulin-stimulated lipogenesis through its transport function rather than transcriptional regulation [#7]. At the organellar level the carrier promotes mitochondrial cristae formation and thereby tunes oxygen consumption, ATP content, and ROS levels [#5]. Biallelic loss-of-function mutations in SLC25A10 cause loss of the protein and its transport activity, complex I deficiency, mitochondrial DNA depletion, and severe epileptic encephalopathy, with transport assays showing the carrier does not transport glutathione [#2]. Biogenesis of the carrier proceeds by a membrane-potential-independent translocation pathway that accumulates a soluble intermembrane-space intermediate distinct from the ADP/ATP carrier import route [#4]. The protein is bound directly by the circadian clock protein CLOCK through defined sites required for its support of glucose homeostasis, redox balance, and electron transport chain function [#3], and it is stabilized against ubiquitination-dependent degradation by MPV17 within an Nrf2–MPV17–SLC25A10 axis governing mitochondrial glutathione handling and ferroptosis [#10]. In cancer contexts SLC25A10 acts downstream of PYCR1 to suppress lipid ROS and ferroptosis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established how the dicarboxylate carrier is delivered to mitochondria, defining a biogenesis route distinct from canonical carrier import.\",\n      \"evidence\": \"In vitro import assays in yeast mitochondria with membrane-potential manipulation, compared against the ADP/ATP carrier\",\n      \"pmids\": [\"11502005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the protein machinery handling the soluble intermembrane-space intermediate\", \"Performed in yeast; human-specific import determinants not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected SLC25A10 transport activity to a metabolic output, showing it supplies malate for citrate export feeding de novo fatty acid synthesis.\",\n      \"evidence\": \"siRNA knockdown in HepG2 and 3T3-L1 cells with citrate transport, ACC1, malonyl-CoA, and triglyceride readouts\",\n      \"pmids\": [\"16027120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selectivity not directly measured in this system\", \"Single lab; in vitro cell models only\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated an organellar structural role, linking carrier abundance to cristae formation and the efficiency of oxidative phosphorylation.\",\n      \"evidence\": \"Overexpression and RNAi of the C. elegans ortholog DIC-1 with cryo-EM cristae morphometry plus ATP, ROS, and paraquat-sensitivity assays\",\n      \"pmids\": [\"19210547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking dicarboxylate transport to cristae remodeling unknown\", \"Ortholog-based; human relevance inferred\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed SLC25A10 in redox and metabolic reprogramming, showing its loss forces oxidative metabolism and impairs NADPH-dependent stress defense in cancer cells.\",\n      \"evidence\": \"siRNA knockdown in A549 cells with metabolic flux, NADPH, ROS, oxygen consumption, and gene-expression readouts\",\n      \"pmids\": [\"25797253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between transport flux and HIF-1α/LDH/GDH changes not resolved\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished transport function from transcriptional effects, showing the carrier supports adipocyte insulin-stimulated lipogenesis directly.\",\n      \"evidence\": \"siRNA knockdown in differentiated human adipocytes with lipogenesis assay and microarray transcriptome profiling\",\n      \"pmids\": [\"28570579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define which transported metabolite mediates the insulin effect\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided human genetic proof of essentiality, tying loss of the carrier to mitochondrial respiratory failure and disease, and excluding glutathione as a substrate at that point.\",\n      \"evidence\": \"Whole-exome sequencing of a patient, fibroblast functional analysis, yeast ortholog knockout, and transport assays\",\n      \"pmids\": [\"29211846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking transport loss to mtDNA depletion and complex I deficiency unresolved\", \"Single patient\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tested pharmacological modulation, linking metformin action on cancer metabolism to suppression of SLC25A10 expression.\",\n      \"evidence\": \"siRNA knockdown plus metformin treatment in A549 cells with qRT-PCR, western blot, and CDKN1A readouts\",\n      \"pmids\": [\"30222970\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression-only correlation; no direct transport or mechanistic assay\", \"Causality between metformin and SLC25A10 not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a direct protein partner, showing CLOCK binds defined SLC25A10 sites that are functionally required for glucose homeostasis and ETC support.\",\n      \"evidence\": \"Reciprocal Co-IP, CRISPR/Cas9 knockout, and rescue with wild-type versus CLOCK-binding-site mutant in Hepa1-6 cells\",\n      \"pmids\": [\"30943427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the CLOCK–SLC25A10 interaction at the molecular level unclear\", \"No structural model of the interaction\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked SLC25A10 to proliferative control in tumor cells via cell-cycle protein regulation.\",\n      \"evidence\": \"shRNA knockdown in osteosarcoma cells with proliferation, apoptosis, mitosis, and CCNE1/P21/P27 readouts\",\n      \"pmids\": [\"32774476\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic link between transport activity and cell-cycle protein regulation\", \"Single knockdown approach\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned SLC25A10 as a ferroptosis-suppressing effector downstream of PYCR1 in cancer.\",\n      \"evidence\": \"Knockdown/overexpression epistasis in colorectal cancer cells with lipid ROS, ferroptosis inducer/inhibitor experiments, and in vivo tumor models\",\n      \"pmids\": [\"36104652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which PYCR1 controls SLC25A10 expression unknown\", \"Transported substrate mediating ferroptosis resistance not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a stability-control axis and assigned a glutathione-transport role, showing MPV17 protects SLC25A10 from ubiquitination-dependent degradation to maintain mitochondrial glutathione import.\",\n      \"evidence\": \"MPV17 overexpression, protein stability and ubiquitination assays, and mitochondrial glutathione measurement in cardiomyocyte iron-overload and I/R models\",\n      \"pmids\": [\"39409161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glutathione-transport assignment conflicts with earlier transport assays excluding glutathione (#2)\", \"E3 ligase mediating degradation not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated SLC25A10 as a mediator of cardioprotection, showing its expression is suppressed in I/R injury and restored by mild therapeutic hypothermia.\",\n      \"evidence\": \"Proteomics, siRNA/gene deletion, and mitochondrial apoptosis pathway readouts in H/R cardiomyocytes and I/R rat model\",\n      \"pmids\": [\"38568407\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Proteomics-identified target with only partial genetic validation\", \"No direct transport assay linking carrier function to protection\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The substrate spectrum of SLC25A10 remains unsettled, with transport assays excluding glutathione yet a glutathione-import role asserted via the MPV17 axis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Definitive reconstituted determination of physiological substrates (malate, succinate, phosphate, sulfate, glutathione) is unresolved\", \"Mechanism connecting transport flux to cristae formation and mtDNA maintenance unknown\", \"Structural basis of CLOCK and MPV17 interactions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CLOCK\", \"MPV17\", \"PYCR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}