{"gene":"SLC25A1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2014,"finding":"SLC25A1 (mitochondrial citrate carrier, CIC) is transcriptionally induced by TNFα and IFNγ via NF-κB and STAT1 transcription factors, and the citrate exported from mitochondria via CIC and its downstream metabolic intermediate acetyl-CoA are required for TNFα- or IFNγ-induced nitric oxide and prostaglandin production.","method":"siRNA knockdown, cytokine stimulation, reporter assays, metabolite measurement (nitric oxide, prostaglandins), acetyl-CoA quantification","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined metabolic phenotype, two orthogonal readouts (NO and prostaglandins), single lab","pmids":["25072865"],"is_preprint":false},{"year":2013,"finding":"Recessive loss-of-function mutations in SLC25A1 cause impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling and absence of carrier protein in patient fibroblasts, resulting in combined D-2- and L-2-hydroxyglutaric aciduria.","method":"Stable isotope labeling experiments, patient fibroblast studies, mutation analysis, SLC25A1 protein expression analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional transport assay in patient cells, isotope labeling, replicated across 12 individuals with consistent genotype-phenotype","pmids":["23561848"],"is_preprint":false},{"year":2009,"finding":"Loss of Sea/SLC25A1 (Drosophila ortholog) impairs citrate transport from mitochondria to cytosol, leading to extensive chromosome breakage in mitotic cells, ATR-dependent cell cycle arrest, and dramatic reduction of global histone acetylation. siRNA knockdown of SLC25A1 in human primary fibroblasts similarly causes chromosome breaks and histone acetylation defects, establishing an evolutionarily conserved role in chromosome integrity.","method":"Drosophila genetic mutation, siRNA knockdown in human fibroblasts, chromosomal breakage assay, histone acetylation measurement, cell cycle analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in Drosophila replicated by siRNA in human cells, multiple orthogonal phenotypic readouts (chromosome breaks, histone acetylation, cell cycle arrest)","pmids":["19654186"],"is_preprint":false},{"year":2014,"finding":"Mutations in SLC25A1 encoding the mitochondrial citrate carrier cause neuromuscular junction dysfunction; mutant SLC25A1 protein shows abnormal carrier function in vitro, and SLC25A1 knockdown in zebrafish mirrors human disease with clear neuromuscular junction abnormalities.","method":"In vitro carrier function assay of mutant protein, zebrafish SLC25A1 knockdown model, neuromuscular junction morphology analysis","journal":"Journal of neuromuscular diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mutant function assay plus vertebrate knockdown model, single lab","pmids":["26870663"],"is_preprint":false},{"year":2018,"finding":"SLC25A1 maintains the mitochondrial pool of citrate and redox balance in lung cancer stem cells; its inhibition leads to ROS build-up and inhibition of self-renewal. Resistance to cisplatin or EGFR inhibitors is acquired through SLC25A1-mediated upregulation of mitochondrial activity and induction of stemness.","method":"SLC25A1 inhibition (CTPI-2), ROS measurement, self-renewal assays, cisplatin/EGFR inhibitor combination studies in vitro and in animal models, patient-derived tumor models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with specific inhibitor, in vivo validation, multiple cancer models, single lab","pmids":["29651165"],"is_preprint":false},{"year":2020,"finding":"Slc25a1 inhibition with CTPI-2 halts steatosis and prevents NASH progression; mechanistically, through citrate-dependent activities, Slc25a1 inhibition rewires the lipogenic program, blunts PPARγ signaling, and inhibits gluconeogenic gene expression. Liver-targeted Slc25a1 knockout reveals tissue-specific and dose-dependent functions.","method":"Pharmacological inhibition (CTPI-2), global heterozygous knockout, liver-targeted conditional knockout, gene expression analysis, PPARγ signaling assays, lipid synthesis measurement","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (global KO, liver-specific KO) plus pharmacological inhibition with consistent mechanism, multiple orthogonal readouts","pmids":["31959914"],"is_preprint":false},{"year":2022,"finding":"IRAKM interacts with and phosphorylates the mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to the cytosol and de novo lipogenesis in adipocytes. IRAKM also mediates Pgc1α acetylation via this axis to regulate thermogenic gene expression.","method":"Co-immunoprecipitation, phosphorylation assay, adipocyte-specific IRAKM knockout, IL-1β stimulation, citrate transport measurement, lipogenesis assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing direct IRAKM-Slc25a1 interaction, phosphorylation demonstrated, adipocyte-specific KO with functional phenotype, single lab","pmids":["35585086"],"is_preprint":false},{"year":2025,"finding":"SLC25A1 drives citrate export from mitochondria to the cytosol where ATP citrate lyase (ACLY) converts it to acetyl-CoA; this acetyl-CoA sustains FSP1 acetylation at K168 (by KAT2B, reversed by HDAC3), preventing FSP1 degradation via K29-linked ubiquitin chains. Pharmacological inhibition of SLC25A1 enhances cancer cell susceptibility to ferroptosis in vitro and in vivo.","method":"CRISPR-Cas9 screen of SLC superfamily, genetic knockout, pharmacological inhibition, acetylation assays, ubiquitination assays, ferroptosis assays in vitro and in vivo","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR screen discovery validated by KO and pharmacological inhibition, mechanistic pathway defined with PTM identification (acetylation site, ubiquitin linkage), in vitro and in vivo validation","pmids":["39881208"],"is_preprint":false},{"year":2023,"finding":"Oncogenic KRASG12D upregulates SLC25A1 transcription via GLI1, which directly binds the SLC25A1 promoter; enhanced SLC25A1 expression increases cytosolic citrate, fatty acids, and key lipid metabolism enzymes to drive pancreatic tumorigenesis. High-fat diet further stimulates this KRASG12D-GLI1-SLC25A1 axis.","method":"Genetically engineered mouse models, ChIP (GLI1 binding to SLC25A1 promoter), pharmacological inhibition of SLC25A1 and GLI1, citrate and fatty acid measurements, pancreatic cancer cell studies","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct GLI1-promoter binding, GEMM with pharmacological intervention, mechanistic pathway defined, single lab","pmids":["37695315"],"is_preprint":false},{"year":2022,"finding":"Overexpression of SLC25A1 in mouse forebrain neurons increases steady-state levels of cytosolic citrate and acetyl-CoA, causes disrupted white matter integrity, altered synaptic plasticity and morphology, and produces autistic-like behavior. SLC25A1 upregulation maintains cytosolic acetyl-CoA by supplying citrate for ACLY-mediated conversion.","method":"Neuron-specific SLC25A1 transgenic mouse, behavioral testing, metabolomics (citrate, acetyl-CoA), proteomics and acetyl-proteomics, synaptic morphology analysis","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse with defined biochemical mechanism (citrate-to-acetyl-CoA), multiple orthogonal phenotypic readouts, single lab","pmids":["35203088"],"is_preprint":false},{"year":1996,"finding":"The human mitochondrial citrate transporter gene (SLC25A1, referred to as SLC20A3 at the time) maps to chromosome band 22q11.21 in a region associated with DiGeorge syndrome, velo-cardio-facial syndrome, and schizophrenia.","method":"Human-hamster somatic cell hybrid panel, fluorescence in situ hybridization (FISH)","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytogenetic mapping by FISH and somatic cell hybrids, single lab, localization finding","pmids":["8682495"],"is_preprint":false},{"year":2016,"finding":"A homozygous missense mutation in SLC25A1 (p.Arg198His) putatively situated within substrate-binding site I of the carrier causes reduced mitochondrial spare respiratory capacity, increased glycolytic flux, and reduced cell survival, establishing a functional requirement for this residue in CIC transport activity.","method":"Patient fibroblast functional studies, mitochondrial respirometry, exome sequencing, citrate supplementation experiments","journal":"JIMD reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell functional assays with multiple respiratory readouts, mutation mapping to substrate-binding site, single lab","pmids":["27306203"],"is_preprint":false}],"current_model":"SLC25A1 encodes the inner mitochondrial membrane citrate carrier (CIC) that exports citrate from the mitochondrial matrix to the cytosol in exchange for malate; cytosolic citrate is converted by ACLY to acetyl-CoA, thereby fueling de novo lipogenesis, histone acetylation for chromatin/genome stability, FSP1 acetylation to suppress ferroptosis, and inflammatory mediator (nitric oxide, prostaglandin) production—with its activity regulated transcriptionally by NF-κB/STAT1 (via TNFα/IFNγ), by KRASG12D-GLI1 signaling, and post-translationally by IRAKM-mediated phosphorylation during IL-1β stimulation."},"narrative":{"mechanistic_narrative":"SLC25A1 encodes the inner mitochondrial membrane citrate carrier (CIC) that exports matrix citrate to the cytosol, where it is converted by ATP citrate lyase to acetyl-CoA, coupling mitochondrial metabolism to cytosolic lipogenic and acetylation programs [PMID:23561848, PMID:39881208]. Recessive loss-of-function mutations abolish citrate efflux in patient fibroblasts and cause combined D-2- and L-2-hydroxyglutaric aciduria [PMID:23561848], and substrate-binding-site mutations (p.Arg198His) reduce respiratory capacity and impair transport activity [PMID:27306203]. This carrier function is evolutionarily conserved: loss of the activity in Drosophila and human cells depletes global histone acetylation and produces chromosome breakage with ATR-dependent cell cycle arrest, establishing a role in genome integrity [PMID:19654186]. The cytosolic citrate/acetyl-CoA pool generated by SLC25A1 fuels diverse downstream outputs: de novo lipogenesis and thermogenic gene control via Pgc1α acetylation in adipocytes [PMID:35585086], FSP1 acetylation at K168 that blocks its ubiquitin-mediated degradation and thereby suppresses ferroptosis [PMID:39881208], and inflammatory mediator production [PMID:25072865]. SLC25A1 expression is regulated transcriptionally by NF-κB and STAT1 downstream of TNFα/IFNγ [PMID:25072865] and by oncogenic KRASG12D acting through GLI1, which binds the SLC25A1 promoter to drive lipid metabolism in pancreatic tumorigenesis [PMID:37695315], and post-translationally by IRAKM-mediated phosphorylation during IL-1β signaling [PMID:35585086]. Through these axes SLC25A1 supports cancer stemness and therapy resistance [PMID:29651165], NASH and steatosis progression [PMID:31959914], and neuronal phenotypes when overexpressed [PMID:35203088].","teleology":[{"year":1996,"claim":"Mapping the human citrate transporter gene located it within a disease-associated genomic interval, anchoring later functional and clinical interpretation.","evidence":"FISH and somatic cell hybrid panel mapping to chromosome 22q11.21","pmids":["8682495"],"confidence":"Medium","gaps":["Mapping alone does not establish a causal role in any disease at the locus","No transport function tested"]},{"year":2009,"claim":"Established that citrate export by the carrier is required for global histone acetylation and chromosome integrity, linking a metabolite transporter to genome stability.","evidence":"Drosophila genetic loss-of-function plus siRNA knockdown in human fibroblasts with chromosome breakage, histone acetylation and cell cycle readouts","pmids":["19654186"],"confidence":"High","gaps":["Molecular route from cytosolic citrate to specific histone acetylation marks not fully resolved","ATR activation mechanism downstream of acetylation loss undefined"]},{"year":2013,"claim":"Demonstrated that recessive loss-of-function mutations directly impair mitochondrial citrate efflux in patients, establishing SLC25A1 as a disease gene for combined D-2- and L-2-hydroxyglutaric aciduria.","evidence":"Stable isotope labeling and carrier protein analysis in patient fibroblasts across 12 individuals","pmids":["23561848"],"confidence":"High","gaps":["Mechanism linking citrate efflux loss to accumulation of both 2-hydroxyglutarate enantiomers not fully defined"]},{"year":2014,"claim":"Connected SLC25A1 to inflammatory signaling by showing cytokine-driven transcriptional induction and a metabolic requirement for citrate/acetyl-CoA in producing inflammatory mediators.","evidence":"siRNA knockdown, cytokine stimulation, reporter assays and metabolite measurements (NO, prostaglandins, acetyl-CoA)","pmids":["25072865"],"confidence":"Medium","gaps":["Direct NF-κB/STAT1 binding to the SLC25A1 promoter not shown","Single lab"]},{"year":2014,"claim":"Extended the disease spectrum by showing mutant carrier dysfunction underlies neuromuscular junction defects in a vertebrate model.","evidence":"In vitro mutant carrier assay and zebrafish knockdown with NMJ morphology analysis","pmids":["26870663"],"confidence":"Medium","gaps":["Mechanism linking citrate transport loss to NMJ dysfunction unresolved","Knockdown not complemented by rescue"]},{"year":2016,"claim":"Pinpointed a substrate-binding-site residue as functionally required for transport, linking a missense mutation to bioenergetic consequences.","evidence":"Patient fibroblast respirometry, exome sequencing and citrate supplementation","pmids":["27306203"],"confidence":"Medium","gaps":["Structural confirmation of the residue's role in substrate binding lacking","Single patient"]},{"year":2018,"claim":"Implicated SLC25A1 in maintaining mitochondrial citrate/redox balance to sustain cancer stemness and acquired therapy resistance.","evidence":"Pharmacological inhibition (CTPI-2), ROS and self-renewal assays, cisplatin/EGFR-inhibitor combinations in vitro, in vivo and patient-derived models","pmids":["29651165"],"confidence":"Medium","gaps":["Off-target effects of CTPI-2 not excluded genetically","Single lab"]},{"year":2020,"claim":"Showed that SLC25A1 inhibition rewires hepatic lipogenic and gluconeogenic programs, defining a role in steatosis and NASH progression with tissue-specific dosage effects.","evidence":"CTPI-2 inhibition, global heterozygous and liver-specific conditional knockouts, gene expression and PPARγ/lipid synthesis assays","pmids":["31959914"],"confidence":"High","gaps":["Direct biochemical link between citrate efflux and PPARγ modulation not isolated"]},{"year":2022,"claim":"Identified post-translational regulation of the carrier, with IRAKM binding and phosphorylating SLC25A1 to drive IL-1β-induced citrate export, lipogenesis and Pgc1α acetylation.","evidence":"Co-IP, phosphorylation assays, adipocyte-specific IRAKM knockout, IL-1β stimulation and citrate transport measurement","pmids":["35585086"],"confidence":"Medium","gaps":["Phosphosite(s) on SLC25A1 not mapped","Reciprocal validation of interaction limited","Single lab"]},{"year":2022,"claim":"Demonstrated that SLC25A1 overexpression raises cytosolic citrate/acetyl-CoA and produces neurological and behavioral phenotypes, linking dosage to brain function.","evidence":"Neuron-specific transgenic mouse with metabolomics, acetyl-proteomics, synaptic morphology and behavioral testing","pmids":["35203088"],"confidence":"Medium","gaps":["Specific acetylated substrates driving phenotypes not pinpointed","Single lab"]},{"year":2023,"claim":"Defined an oncogenic transcriptional axis in which KRASG12D-GLI1 directly induces SLC25A1 to boost cytosolic citrate and lipid metabolism for pancreatic tumorigenesis.","evidence":"GEMMs, ChIP of GLI1 at the SLC25A1 promoter, pharmacological inhibition, citrate and fatty acid measurements","pmids":["37695315"],"confidence":"Medium","gaps":["Whether GLI1 acts alone or with cofactors at the promoter unclear","Single lab"]},{"year":2025,"claim":"Resolved a ferroptosis-suppressive mechanism whereby SLC25A1-derived acetyl-CoA sustains FSP1 acetylation at K168, blocking its ubiquitin-mediated degradation.","evidence":"CRISPR-Cas9 SLC screen, knockout and pharmacological inhibition, acetylation/ubiquitination assays and ferroptosis assays in vitro and in vivo","pmids":["39881208"],"confidence":"High","gaps":["Stoichiometry of acetyl-CoA flux to FSP1 acetylation not quantified","KAT2B/HDAC3 recruitment mechanism to FSP1 undefined"]},{"year":null,"claim":"How the diverse cytosolic acetyl-CoA-dependent outputs (histone, FSP1, Pgc1α acetylation; lipogenesis; inflammation) are coordinated and prioritized in a given tissue or disease state remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model of substrate selectivity for the citrate/acetyl-CoA pool","Structural basis of transport and its regulation by phosphorylation not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,2,11]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,5,8]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2]}],"complexes":[],"partners":["IRAKM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P53007","full_name":"Tricarboxylate transport protein, mitochondrial","aliases":["Citrate transport protein","CTP","Mitochondrial citrate carrier","CIC","Solute carrier family 25 member 1","Tricarboxylate carrier protein"],"length_aa":311,"mass_kda":34.0,"function":"Mitochondrial electroneutral antiporter that exports citrate from the mitochondria into the cytosol in exchange for malate (PubMed:26870663, PubMed:29031613, PubMed:29238895, PubMed:39881208, PubMed:38937634). Also able to mediate the exchange of citrate for isocitrate, phosphoenolpyruvate, cis-aconitate and to a lesser extent trans-aconitate, maleate and succinate (PubMed:29031613). 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). In the cytoplasm, citrate plays important roles in fatty acid and sterol synthesis, regulation of glycolysis, protein acetylation, and other physiopathological processes (PubMed:29031613, PubMed:29238895, PubMed:39881208)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P53007/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC25A1","classification":"Not Classified","n_dependent_lines":192,"n_total_lines":1208,"dependency_fraction":0.15894039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC25A1","total_profiled":1310},"omim":[{"mim_id":"618197","title":"MYASTHENIC SYNDROME, CONGENITAL, 23, PRESYNAPTIC; CMS23","url":"https://www.omim.org/entry/618197"},{"mim_id":"615182","title":"COMBINED D-2- AND L-2-HYDROXYGLUTARIC ACIDURIA; D2L2AD","url":"https://www.omim.org/entry/615182"},{"mim_id":"601462","title":"MYASTHENIC SYNDROME, CONGENITAL, 1A, SLOW-CHANNEL; CMS1A","url":"https://www.omim.org/entry/601462"},{"mim_id":"300212","title":"REGUCALCIN; RGN","url":"https://www.omim.org/entry/300212"},{"mim_id":"192430","title":"VELOCARDIOFACIAL SYNDROME; VCFS","url":"https://www.omim.org/entry/192430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":206.9}],"url":"https://www.proteinatlas.org/search/SLC25A1"},"hgnc":{"alias_symbol":["CTP","CIC"],"prev_symbol":["SLC20A3"]},"alphafold":{"accession":"P53007","domains":[{"cath_id":"-","chopping":"186-278","consensus_level":"medium","plddt":78.7845,"start":186,"end":278}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53007","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53007-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53007-F1-predicted_aligned_error_v6.png","plddt_mean":74.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC25A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC25A1"},"sequence":{"accession":"P53007","fasta_url":"https://rest.uniprot.org/uniprotkb/P53007.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53007/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53007"}},"corpus_meta":[{"pmid":"20639870","id":"PMC_20639870","title":"The 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transcriptionally induced by TNFα and IFNγ via NF-κB and STAT1 transcription factors, and the citrate exported from mitochondria via CIC and its downstream metabolic intermediate acetyl-CoA are required for TNFα- or IFNγ-induced nitric oxide and prostaglandin production.\",\n      \"method\": \"siRNA knockdown, cytokine stimulation, reporter assays, metabolite measurement (nitric oxide, prostaglandins), acetyl-CoA quantification\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined metabolic phenotype, two orthogonal readouts (NO and prostaglandins), single lab\",\n      \"pmids\": [\"25072865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Recessive loss-of-function mutations in SLC25A1 cause impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling and absence of carrier protein in patient fibroblasts, resulting in combined D-2- and L-2-hydroxyglutaric aciduria.\",\n      \"method\": \"Stable isotope labeling experiments, patient fibroblast studies, mutation analysis, SLC25A1 protein expression analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional transport assay in patient cells, isotope labeling, replicated across 12 individuals with consistent genotype-phenotype\",\n      \"pmids\": [\"23561848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss of Sea/SLC25A1 (Drosophila ortholog) impairs citrate transport from mitochondria to cytosol, leading to extensive chromosome breakage in mitotic cells, ATR-dependent cell cycle arrest, and dramatic reduction of global histone acetylation. siRNA knockdown of SLC25A1 in human primary fibroblasts similarly causes chromosome breaks and histone acetylation defects, establishing an evolutionarily conserved role in chromosome integrity.\",\n      \"method\": \"Drosophila genetic mutation, siRNA knockdown in human fibroblasts, chromosomal breakage assay, histone acetylation measurement, cell cycle analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in Drosophila replicated by siRNA in human cells, multiple orthogonal phenotypic readouts (chromosome breaks, histone acetylation, cell cycle arrest)\",\n      \"pmids\": [\"19654186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutations in SLC25A1 encoding the mitochondrial citrate carrier cause neuromuscular junction dysfunction; mutant SLC25A1 protein shows abnormal carrier function in vitro, and SLC25A1 knockdown in zebrafish mirrors human disease with clear neuromuscular junction abnormalities.\",\n      \"method\": \"In vitro carrier function assay of mutant protein, zebrafish SLC25A1 knockdown model, neuromuscular junction morphology analysis\",\n      \"journal\": \"Journal of neuromuscular diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mutant function assay plus vertebrate knockdown model, single lab\",\n      \"pmids\": [\"26870663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC25A1 maintains the mitochondrial pool of citrate and redox balance in lung cancer stem cells; its inhibition leads to ROS build-up and inhibition of self-renewal. Resistance to cisplatin or EGFR inhibitors is acquired through SLC25A1-mediated upregulation of mitochondrial activity and induction of stemness.\",\n      \"method\": \"SLC25A1 inhibition (CTPI-2), ROS measurement, self-renewal assays, cisplatin/EGFR inhibitor combination studies in vitro and in animal models, patient-derived tumor models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with specific inhibitor, in vivo validation, multiple cancer models, single lab\",\n      \"pmids\": [\"29651165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Slc25a1 inhibition with CTPI-2 halts steatosis and prevents NASH progression; mechanistically, through citrate-dependent activities, Slc25a1 inhibition rewires the lipogenic program, blunts PPARγ signaling, and inhibits gluconeogenic gene expression. Liver-targeted Slc25a1 knockout reveals tissue-specific and dose-dependent functions.\",\n      \"method\": \"Pharmacological inhibition (CTPI-2), global heterozygous knockout, liver-targeted conditional knockout, gene expression analysis, PPARγ signaling assays, lipid synthesis measurement\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (global KO, liver-specific KO) plus pharmacological inhibition with consistent mechanism, multiple orthogonal readouts\",\n      \"pmids\": [\"31959914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IRAKM interacts with and phosphorylates the mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to the cytosol and de novo lipogenesis in adipocytes. IRAKM also mediates Pgc1α acetylation via this axis to regulate thermogenic gene expression.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, adipocyte-specific IRAKM knockout, IL-1β stimulation, citrate transport measurement, lipogenesis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing direct IRAKM-Slc25a1 interaction, phosphorylation demonstrated, adipocyte-specific KO with functional phenotype, single lab\",\n      \"pmids\": [\"35585086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A1 drives citrate export from mitochondria to the cytosol where ATP citrate lyase (ACLY) converts it to acetyl-CoA; this acetyl-CoA sustains FSP1 acetylation at K168 (by KAT2B, reversed by HDAC3), preventing FSP1 degradation via K29-linked ubiquitin chains. Pharmacological inhibition of SLC25A1 enhances cancer cell susceptibility to ferroptosis in vitro and in vivo.\",\n      \"method\": \"CRISPR-Cas9 screen of SLC superfamily, genetic knockout, pharmacological inhibition, acetylation assays, ubiquitination assays, ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR screen discovery validated by KO and pharmacological inhibition, mechanistic pathway defined with PTM identification (acetylation site, ubiquitin linkage), in vitro and in vivo validation\",\n      \"pmids\": [\"39881208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oncogenic KRASG12D upregulates SLC25A1 transcription via GLI1, which directly binds the SLC25A1 promoter; enhanced SLC25A1 expression increases cytosolic citrate, fatty acids, and key lipid metabolism enzymes to drive pancreatic tumorigenesis. High-fat diet further stimulates this KRASG12D-GLI1-SLC25A1 axis.\",\n      \"method\": \"Genetically engineered mouse models, ChIP (GLI1 binding to SLC25A1 promoter), pharmacological inhibition of SLC25A1 and GLI1, citrate and fatty acid measurements, pancreatic cancer cell studies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct GLI1-promoter binding, GEMM with pharmacological intervention, mechanistic pathway defined, single lab\",\n      \"pmids\": [\"37695315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of SLC25A1 in mouse forebrain neurons increases steady-state levels of cytosolic citrate and acetyl-CoA, causes disrupted white matter integrity, altered synaptic plasticity and morphology, and produces autistic-like behavior. SLC25A1 upregulation maintains cytosolic acetyl-CoA by supplying citrate for ACLY-mediated conversion.\",\n      \"method\": \"Neuron-specific SLC25A1 transgenic mouse, behavioral testing, metabolomics (citrate, acetyl-CoA), proteomics and acetyl-proteomics, synaptic morphology analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse with defined biochemical mechanism (citrate-to-acetyl-CoA), multiple orthogonal phenotypic readouts, single lab\",\n      \"pmids\": [\"35203088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human mitochondrial citrate transporter gene (SLC25A1, referred to as SLC20A3 at the time) maps to chromosome band 22q11.21 in a region associated with DiGeorge syndrome, velo-cardio-facial syndrome, and schizophrenia.\",\n      \"method\": \"Human-hamster somatic cell hybrid panel, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytogenetic mapping by FISH and somatic cell hybrids, single lab, localization finding\",\n      \"pmids\": [\"8682495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous missense mutation in SLC25A1 (p.Arg198His) putatively situated within substrate-binding site I of the carrier causes reduced mitochondrial spare respiratory capacity, increased glycolytic flux, and reduced cell survival, establishing a functional requirement for this residue in CIC transport activity.\",\n      \"method\": \"Patient fibroblast functional studies, mitochondrial respirometry, exome sequencing, citrate supplementation experiments\",\n      \"journal\": \"JIMD reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell functional assays with multiple respiratory readouts, mutation mapping to substrate-binding site, single lab\",\n      \"pmids\": [\"27306203\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A1 encodes the inner mitochondrial membrane citrate carrier (CIC) that exports citrate from the mitochondrial matrix to the cytosol in exchange for malate; cytosolic citrate is converted by ACLY to acetyl-CoA, thereby fueling de novo lipogenesis, histone acetylation for chromatin/genome stability, FSP1 acetylation to suppress ferroptosis, and inflammatory mediator (nitric oxide, prostaglandin) production—with its activity regulated transcriptionally by NF-κB/STAT1 (via TNFα/IFNγ), by KRASG12D-GLI1 signaling, and post-translationally by IRAKM-mediated phosphorylation during IL-1β stimulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC25A1 encodes the inner mitochondrial membrane citrate carrier (CIC) that exports matrix citrate to the cytosol, where it is converted by ATP citrate lyase to acetyl-CoA, coupling mitochondrial metabolism to cytosolic lipogenic and acetylation programs [#1, #7]. Recessive loss-of-function mutations abolish citrate efflux in patient fibroblasts and cause combined D-2- and L-2-hydroxyglutaric aciduria [#1], and substrate-binding-site mutations (p.Arg198His) reduce respiratory capacity and impair transport activity [#11]. This carrier function is evolutionarily conserved: loss of the activity in Drosophila and human cells depletes global histone acetylation and produces chromosome breakage with ATR-dependent cell cycle arrest, establishing a role in genome integrity [#2]. The cytosolic citrate/acetyl-CoA pool generated by SLC25A1 fuels diverse downstream outputs: de novo lipogenesis and thermogenic gene control via Pgc1\\u03b1 acetylation in adipocytes [#6], FSP1 acetylation at K168 that blocks its ubiquitin-mediated degradation and thereby suppresses ferroptosis [#7], and inflammatory mediator production [#0]. SLC25A1 expression is regulated transcriptionally by NF-\\u03baB and STAT1 downstream of TNF\\u03b1/IFN\\u03b3 [#0] and by oncogenic KRASG12D acting through GLI1, which binds the SLC25A1 promoter to drive lipid metabolism in pancreatic tumorigenesis [#8], and post-translationally by IRAKM-mediated phosphorylation during IL-1\\u03b2 signaling [#6]. Through these axes SLC25A1 supports cancer stemness and therapy resistance [#4], NASH and steatosis progression [#5], and neuronal phenotypes when overexpressed [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapping the human citrate transporter gene located it within a disease-associated genomic interval, anchoring later functional and clinical interpretation.\",\n      \"evidence\": \"FISH and somatic cell hybrid panel mapping to chromosome 22q11.21\",\n      \"pmids\": [\"8682495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapping alone does not establish a causal role in any disease at the locus\", \"No transport function tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that citrate export by the carrier is required for global histone acetylation and chromosome integrity, linking a metabolite transporter to genome stability.\",\n      \"evidence\": \"Drosophila genetic loss-of-function plus siRNA knockdown in human fibroblasts with chromosome breakage, histone acetylation and cell cycle readouts\",\n      \"pmids\": [\"19654186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular route from cytosolic citrate to specific histone acetylation marks not fully resolved\", \"ATR activation mechanism downstream of acetylation loss undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that recessive loss-of-function mutations directly impair mitochondrial citrate efflux in patients, establishing SLC25A1 as a disease gene for combined D-2- and L-2-hydroxyglutaric aciduria.\",\n      \"evidence\": \"Stable isotope labeling and carrier protein analysis in patient fibroblasts across 12 individuals\",\n      \"pmids\": [\"23561848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking citrate efflux loss to accumulation of both 2-hydroxyglutarate enantiomers not fully defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected SLC25A1 to inflammatory signaling by showing cytokine-driven transcriptional induction and a metabolic requirement for citrate/acetyl-CoA in producing inflammatory mediators.\",\n      \"evidence\": \"siRNA knockdown, cytokine stimulation, reporter assays and metabolite measurements (NO, prostaglandins, acetyl-CoA)\",\n      \"pmids\": [\"25072865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NF-\\u03baB/STAT1 binding to the SLC25A1 promoter not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the disease spectrum by showing mutant carrier dysfunction underlies neuromuscular junction defects in a vertebrate model.\",\n      \"evidence\": \"In vitro mutant carrier assay and zebrafish knockdown with NMJ morphology analysis\",\n      \"pmids\": [\"26870663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking citrate transport loss to NMJ dysfunction unresolved\", \"Knockdown not complemented by rescue\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pinpointed a substrate-binding-site residue as functionally required for transport, linking a missense mutation to bioenergetic consequences.\",\n      \"evidence\": \"Patient fibroblast respirometry, exome sequencing and citrate supplementation\",\n      \"pmids\": [\"27306203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural confirmation of the residue's role in substrate binding lacking\", \"Single patient\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated SLC25A1 in maintaining mitochondrial citrate/redox balance to sustain cancer stemness and acquired therapy resistance.\",\n      \"evidence\": \"Pharmacological inhibition (CTPI-2), ROS and self-renewal assays, cisplatin/EGFR-inhibitor combinations in vitro, in vivo and patient-derived models\",\n      \"pmids\": [\"29651165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Off-target effects of CTPI-2 not excluded genetically\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that SLC25A1 inhibition rewires hepatic lipogenic and gluconeogenic programs, defining a role in steatosis and NASH progression with tissue-specific dosage effects.\",\n      \"evidence\": \"CTPI-2 inhibition, global heterozygous and liver-specific conditional knockouts, gene expression and PPAR\\u03b3/lipid synthesis assays\",\n      \"pmids\": [\"31959914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between citrate efflux and PPAR\\u03b3 modulation not isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-translational regulation of the carrier, with IRAKM binding and phosphorylating SLC25A1 to drive IL-1\\u03b2-induced citrate export, lipogenesis and Pgc1\\u03b1 acetylation.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, adipocyte-specific IRAKM knockout, IL-1\\u03b2 stimulation and citrate transport measurement\",\n      \"pmids\": [\"35585086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite(s) on SLC25A1 not mapped\", \"Reciprocal validation of interaction limited\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that SLC25A1 overexpression raises cytosolic citrate/acetyl-CoA and produces neurological and behavioral phenotypes, linking dosage to brain function.\",\n      \"evidence\": \"Neuron-specific transgenic mouse with metabolomics, acetyl-proteomics, synaptic morphology and behavioral testing\",\n      \"pmids\": [\"35203088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific acetylated substrates driving phenotypes not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined an oncogenic transcriptional axis in which KRASG12D-GLI1 directly induces SLC25A1 to boost cytosolic citrate and lipid metabolism for pancreatic tumorigenesis.\",\n      \"evidence\": \"GEMMs, ChIP of GLI1 at the SLC25A1 promoter, pharmacological inhibition, citrate and fatty acid measurements\",\n      \"pmids\": [\"37695315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GLI1 acts alone or with cofactors at the promoter unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a ferroptosis-suppressive mechanism whereby SLC25A1-derived acetyl-CoA sustains FSP1 acetylation at K168, blocking its ubiquitin-mediated degradation.\",\n      \"evidence\": \"CRISPR-Cas9 SLC screen, knockout and pharmacological inhibition, acetylation/ubiquitination assays and ferroptosis assays in vitro and in vivo\",\n      \"pmids\": [\"39881208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of acetyl-CoA flux to FSP1 acetylation not quantified\", \"KAT2B/HDAC3 recruitment mechanism to FSP1 undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse cytosolic acetyl-CoA-dependent outputs (histone, FSP1, Pgc1\\u03b1 acetylation; lipogenesis; inflammation) are coordinated and prioritized in a given tissue or disease state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model of substrate selectivity for the citrate/acetyl-CoA pool\", \"Structural basis of transport and its regulation by phosphorylation not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IRAKM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}