{"gene":"MTX1","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":1996,"finding":"The human MTX1 gene encodes a 317 amino acid mitochondrial protein. The predicted protein lacks an amino-terminal signal sequence and N-glycosylation sites but contains a putative transmembrane domain near its carboxy terminus. MTX1 is contiguous to THBS3 (sharing a common promoter region) and to the glucocerebrosidase pseudogene (psGBA), and a pseudogene for metaxin (psMTX) was identified within the GBA locus region. In liver, the pseudogene is not expressed.","method":"cDNA sequencing, genomic cloning, exon-intron mapping, Northern blot expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic and cDNA sequencing with expression analysis in a single focused study; structural features (transmembrane domain, lack of signal sequence) inferred from sequence prediction rather than experimental validation","pmids":["8660965"],"is_preprint":false},{"year":2021,"finding":"MTX1 (Metaxin 1) overexpression promotes sorafenib resistance in hepatocellular carcinoma cells by augmenting autophagy. Mechanistically, MTX1 interacts with and inhibits CISD1 (CDGSH iron sulfur domain 1), a negative regulator of autophagy; loss of CISD1 activity leads to increased autophagy flux that confers drug resistance. MTX1 overexpression increased cell proliferation and decreased apoptosis upon sorafenib treatment both in vitro and in a subcutaneous xenograft model.","method":"CRISPRa genome-scale screening, co-immunoprecipitation (MTX1-CISD1 interaction), loss-of-function/gain-of-function experiments, in vitro cell proliferation/apoptosis assays, subcutaneous xenograft tumor model","journal":"International Journal of Biological Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified by Co-IP, functional rescue experiments in vitro and in vivo, single lab with multiple orthogonal methods","pmids":["34421355"],"is_preprint":false},{"year":2011,"finding":"The MTX1 c.184T>A (p.S63T) variant is found at high frequency in Ashkenazi GBA mutation carriers (allele frequency 0.67 vs 0.45 in non-carriers). Homozygosity for the MTX1 c.184A/A genotype is associated with significantly earlier age of motor symptom onset (5.1–5.9 years younger) in GBA-associated Parkinson's disease patients, suggesting that MTX1 variation on the allele trans to the GBA mutation can modify the clinical course of GBA-associated PD.","method":"Genotyping of MTX1 coding region in 600 Ashkenazi PD patients and 353 controls; statistical association analysis with age of onset","journal":"Neurogenetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic association study without functional mechanistic follow-up; no direct experiment on MTX1 protein function; single cohort","pmids":["21837367"],"is_preprint":false}],"current_model":"MTX1 (Metaxin 1) encodes a mitochondrial outer membrane protein with a C-terminal transmembrane domain and no amino-terminal signal sequence; it physically interacts with CISD1 (an autophagy negative regulator) and, when overexpressed, promotes autophagy-mediated sorafenib resistance in hepatocellular carcinoma, while a common coding variant (p.S63T) in linkage with GBA mutations modifies age of onset in Parkinson's disease."},"narrative":{"mechanistic_narrative":"MTX1 (Metaxin 1) is a mitochondrial protein that influences autophagy and, through it, cell survival under stress [PMID:8660965, PMID:34421355]. It is a 317-residue protein that lacks an amino-terminal signal sequence but carries a putative transmembrane domain near its carboxy terminus, consistent with a tail-anchored topology in the mitochondrial outer membrane [PMID:8660965]. Functionally, MTX1 physically interacts with and inhibits CISD1, a negative regulator of autophagy; this interaction relieves CISD1's restraint on autophagic flux, and MTX1 overexpression thereby augments autophagy to promote sorafenib resistance, increased proliferation, and reduced apoptosis in hepatocellular carcinoma cells and xenografts [PMID:34421355]. The MTX1 gene resides at the GBA locus, and a coding variant (p.S63T) on the allele trans to GBA mutations is associated with earlier age of motor symptom onset in GBA-associated Parkinson's disease [PMID:8660965, PMID:21837367]. Beyond these findings, the biochemical basis of MTX1's transmembrane insertion and the structural detail of the MTX1-CISD1 interface have not been characterized in the available corpus.","teleology":[{"year":1996,"claim":"Established the molecular identity of human MTX1 as a mitochondrial protein with a defined topology and genomic context, framing it as a tail-anchored outer-membrane candidate rather than a secreted or matrix protein.","evidence":"cDNA sequencing, genomic cloning, exon-intron mapping, and Northern blot in human tissues","pmids":["8660965"],"confidence":"Medium","gaps":["Transmembrane domain and lack of signal sequence inferred from sequence prediction, not experimentally validated","Submitochondrial localization and membrane orientation not directly demonstrated","No functional role assigned"]},{"year":2011,"claim":"Connected MTX1 sequence variation to clinical phenotype, showing the p.S63T variant on the trans allele modifies age of onset in GBA-associated Parkinson's disease.","evidence":"Genotyping of MTX1 coding region in 600 Ashkenazi PD patients and 353 controls with age-of-onset association analysis","pmids":["21837367"],"confidence":"Low","gaps":["Genetic association without functional mechanistic follow-up","No direct experiment on MTX1 protein function","Single cohort; linkage with GBA confounds attribution to MTX1"]},{"year":2021,"claim":"Defined a direct molecular mechanism for MTX1 in autophagy regulation, showing it inhibits CISD1 to drive autophagy-mediated drug resistance in cancer.","evidence":"CRISPRa genome-scale screen, MTX1-CISD1 co-immunoprecipitation, gain/loss-of-function assays, and subcutaneous xenograft model in hepatocellular carcinoma","pmids":["34421355"],"confidence":"Medium","gaps":["Interaction shown by Co-IP without structural definition of the binding interface","Mechanism by which CISD1 inhibition increases autophagy flux not resolved at the molecular level","Demonstrated in HCC context; generality across tissues unknown"]},{"year":null,"claim":"How MTX1's outer-membrane topology relates to its CISD1-dependent autophagy function, and whether the Parkinson's-associated variant alters this activity, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the MTX1-CISD1 complex","No link established between the p.S63T variant and any biochemical or autophagy phenotype","Membrane insertion mechanism not experimentally characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]}],"complexes":[],"partners":["CISD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13505","full_name":"Metaxin-1","aliases":["Mitochondrial outer membrane import complex protein 1"],"length_aa":466,"mass_kda":51.5,"function":"Involved in transport of proteins into the mitochondrion. Essential for embryonic development (By similarity)","subcellular_location":"Membrane; Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q13505/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTX1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DNAJC11","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/MTX1","total_profiled":1310},"omim":[{"mim_id":"615634","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 6; CHCHD6","url":"https://www.omim.org/entry/615634"},{"mim_id":"613748","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 3; CHCHD3","url":"https://www.omim.org/entry/613748"},{"mim_id":"612058","title":"SAMM50 SORTING AND ASSEMBLY MACHINERY COMPONENT; SAMM50","url":"https://www.omim.org/entry/612058"},{"mim_id":"608555","title":"METAXIN 2; MTX2","url":"https://www.omim.org/entry/608555"},{"mim_id":"600605","title":"METAXIN 1; MTX1","url":"https://www.omim.org/entry/600605"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTX1"},"hgnc":{"alias_symbol":["MTXN"],"prev_symbol":["MTX"]},"alphafold":{"accession":"Q13505","domains":[{"cath_id":"1.20.1050.10","chopping":"156-392","consensus_level":"medium","plddt":93.393,"start":156,"end":392}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13505","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13505-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13505-F1-predicted_aligned_error_v6.png","plddt_mean":71.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTX1","jax_strain_url":"https://www.jax.org/strain/search?query=MTX1"},"sequence":{"accession":"Q13505","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13505.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13505/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13505"}},"corpus_meta":[{"pmid":"10664539","id":"PMC_10664539","title":"Caco-2 versus Caco-2/HT29-MTX 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and MR imaging.","date":"2017","source":"Drug development and industrial pharmacy","url":"https://pubmed.ncbi.nlm.nih.gov/29098882","citation_count":26,"is_preprint":false},{"pmid":"24754871","id":"PMC_24754871","title":"Synthetic polyglutamylation of dual-functional MTX ligands for enhanced combined cytotoxicity of poly(I:C) nanoplexes.","date":"2014","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/24754871","citation_count":25,"is_preprint":false},{"pmid":"29746672","id":"PMC_29746672","title":"Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes.","date":"2018","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29746672","citation_count":24,"is_preprint":false},{"pmid":"21339747","id":"PMC_21339747","title":"Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis.","date":"2011","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21339747","citation_count":24,"is_preprint":false},{"pmid":"28726765","id":"PMC_28726765","title":"Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28726765","citation_count":24,"is_preprint":false},{"pmid":"23622764","id":"PMC_23622764","title":"CD147 promotes MTX resistance by immune cells through up-regulating ABCG2 expression and function.","date":"2013","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/23622764","citation_count":23,"is_preprint":false},{"pmid":"23300841","id":"PMC_23300841","title":"Fusion of the Dhfr/Mtx and IR/MAR gene amplification methods produces a rapid and efficient method for stable recombinant protein production.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23300841","citation_count":23,"is_preprint":false},{"pmid":"21399669","id":"PMC_21399669","title":"The role of HLA--G 14-bp polymorphism in allo-HSCT after short-term course MTX for GvHD prophylaxis.","date":"2011","source":"Bone marrow transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/21399669","citation_count":23,"is_preprint":false},{"pmid":"30847127","id":"PMC_30847127","title":"Effects of chlorogenic acid, epicatechin gallate, and quercetin on mucin expression and secretion in the Caco-2/HT29-MTX cell model.","date":"2019","source":"Food science & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/30847127","citation_count":21,"is_preprint":false},{"pmid":"31115880","id":"PMC_31115880","title":"Systemic HD-MTX for CNS prophylaxis in high-risk DLBCL patients: a prospectively collected, single-center cohort analysis.","date":"2019","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/31115880","citation_count":21,"is_preprint":false},{"pmid":"34346513","id":"PMC_34346513","title":"Association of MTHFR and ABCB1 polymorphisms with MTX-induced mucositis in Chinese paediatric patients with acute lymphoblastic leukaemia, lymphoma or osteosarcoma-A retrospective cohort study.","date":"2021","source":"Journal of clinical pharmacy and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34346513","citation_count":20,"is_preprint":false},{"pmid":"22416214","id":"PMC_22416214","title":"Effect of 5-FU and MTX on the Expression of Drug-resistance Related Cancer Stem Cell Markers in Non-small Cell Lung Cancer Cells.","date":"2012","source":"The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22416214","citation_count":20,"is_preprint":false},{"pmid":"33254900","id":"PMC_33254900","title":"Repeated exposure of Caco-2 versus Caco-2/HT29-MTX intestinal cell models to (nano)silver in vitro: Comparison of two commercially available colloidal silver products.","date":"2020","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/33254900","citation_count":20,"is_preprint":false},{"pmid":"34928974","id":"PMC_34928974","title":"Characterization of increased mucus production of HT29-MTX-E12 cells grown under Semi-Wet interface with Mechanical Stimulation.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34928974","citation_count":19,"is_preprint":false},{"pmid":"32414668","id":"PMC_32414668","title":"Silencing DVL3 defeats MTX resistance and attenuates stemness via Notch Signaling Pathway in colorectal cancer.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/32414668","citation_count":18,"is_preprint":false},{"pmid":"31824157","id":"PMC_31824157","title":"Preparation and Characterization of Fe3O4@MTX Magnetic Nanoparticles for Thermochemotherapy of Primary Central Nervous System Lymphoma in vitro and in vivo.","date":"2019","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31824157","citation_count":18,"is_preprint":false},{"pmid":"25124602","id":"PMC_25124602","title":"Novel DOX-MTX nanoparticles improve oral SCC clinical outcome by down regulation of lymph dissemination factor VEGF-C expression in vivo: oral and IV modalities.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/25124602","citation_count":18,"is_preprint":false},{"pmid":"6884005","id":"PMC_6884005","title":"Characterization of two paralysing protein toxins (A-MTX and B-MTX), isolated from a homogenate of the wasp Microbracon hebetor (Say).","date":"1983","source":"Comparative biochemistry and physiology. B, Comparative biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6884005","citation_count":18,"is_preprint":false},{"pmid":"29931006","id":"PMC_29931006","title":"The impact of apical and basolateral albumin on intestinal zinc resorption in the Caco-2/HT-29-MTX co-culture model.","date":"2018","source":"Metallomics : integrated biometal science","url":"https://pubmed.ncbi.nlm.nih.gov/29931006","citation_count":18,"is_preprint":false},{"pmid":"35157101","id":"PMC_35157101","title":"Evaluation of cytogenetic and molecular markers with MTX-mediated toxicity in pediatric acute lymphoblastic leukemia patients.","date":"2022","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35157101","citation_count":17,"is_preprint":false},{"pmid":"16882589","id":"PMC_16882589","title":"The effect of methotrexate (MTX) on expression of signalling lymphocytic activation molecule (SLAM) in patients with rheumatoid arthritis (RA) and its role in the regulation of cytokine production.","date":"2006","source":"Scandinavian journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/16882589","citation_count":17,"is_preprint":false},{"pmid":"36635685","id":"PMC_36635685","title":"MTX-PEG-modified CG/DMMA polymeric micelles for targeted delivery of doxorubicin to induce synergistic autophagic death against triple-negative breast cancer.","date":"2023","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/36635685","citation_count":17,"is_preprint":false},{"pmid":"37765306","id":"PMC_37765306","title":"Caco-2 Cell Sheet Partially Laminated with HT29-MTX Cells as a Novel In Vitro Model of Gut Epithelium Drug Permeability.","date":"2023","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/37765306","citation_count":16,"is_preprint":false},{"pmid":"26632501","id":"PMC_26632501","title":"Ubiquitous Chromatin Opening Elements (UCOEs) effect on transgene position and expression stability in CHO cells following methotrexate (MTX) amplification.","date":"2016","source":"Biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/26632501","citation_count":16,"is_preprint":false},{"pmid":"24845150","id":"PMC_24845150","title":"Impact analysis of autoantibody level and NR2 antibody level in neuropsychiatric SLE treated by methylprednisolone combined with MTX and DXM intrathecal injection.","date":"2014","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/24845150","citation_count":16,"is_preprint":false},{"pmid":"21837367","id":"PMC_21837367","title":"Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age of onset in GBA-associated Parkinson's disease.","date":"2011","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21837367","citation_count":15,"is_preprint":false},{"pmid":"37108769","id":"PMC_37108769","title":"MTX-211 Inhibits GSH Synthesis through Keap1/NRF2/GCLM Axis and Exerts Antitumor Effects in Bladder Cancer.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37108769","citation_count":15,"is_preprint":false},{"pmid":"35322376","id":"PMC_35322376","title":"ADSC-Exosomes Alleviate MTX-induced Rat Neuronal Damage by Activating Nrf2-ARE Pathway.","date":"2022","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/35322376","citation_count":15,"is_preprint":false},{"pmid":"2465288","id":"PMC_2465288","title":"Impairment of methotrexate (MTX)-polyglutamate formation of MTX-resistant K562 cell lines.","date":"1988","source":"Japanese journal of cancer research : Gann","url":"https://pubmed.ncbi.nlm.nih.gov/2465288","citation_count":15,"is_preprint":false},{"pmid":"25661354","id":"PMC_25661354","title":"Synthesis and formulation of methotrexate (MTX) conjugated LaF3:Tb(3+)/chitosan nanoparticles for targeted drug delivery applications.","date":"2014","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/25661354","citation_count":15,"is_preprint":false},{"pmid":"25339032","id":"PMC_25339032","title":"DOX-MTX-NPs augment p53 mRNA expression in OSCC model in rat: effects of IV and oral routes.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/25339032","citation_count":15,"is_preprint":false},{"pmid":"23334376","id":"PMC_23334376","title":"Combination of MTX and LEF attenuates inflammatory bone erosion by down-regulation of receptor activator of NF-kB ligand and interleukin-17 in type II collagen-induced arthritis rats.","date":"2013","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/23334376","citation_count":15,"is_preprint":false},{"pmid":"29863797","id":"PMC_29863797","title":"Effects of Lactobacillus rhamnosus GG and Escherichia coli Nissle 1917 Cell-Free Supernatants on Modulation of Mucin and Cytokine Secretion on Human Intestinal Epithelial HT29-MTX Cells.","date":"2018","source":"Journal of food science","url":"https://pubmed.ncbi.nlm.nih.gov/29863797","citation_count":15,"is_preprint":false},{"pmid":"9712088","id":"PMC_9712088","title":"Longterm combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy.","date":"1998","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/9712088","citation_count":15,"is_preprint":false},{"pmid":"39065818","id":"PMC_39065818","title":"A First Metabolite Analysis of Norfolk Island Pine Resin and Its Hepatoprotective Potential to Alleviate Methotrexate (MTX)-Induced Hepatic Injury.","date":"2024","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39065818","citation_count":15,"is_preprint":false},{"pmid":"7694891","id":"PMC_7694891","title":"Intrinsic resistance of cervical squamous cell carcinoma cell lines to methotrexate (MTX) as a result of decreased accumulation of intracellular MTX polyglutamates.","date":"1993","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/7694891","citation_count":15,"is_preprint":false},{"pmid":"24525490","id":"PMC_24525490","title":"Effect of edible oils on quercetin, kaempferol and galangin transport and conjugation in the intestinal Caco-2/HT29-MTX co-culture model.","date":"2014","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/24525490","citation_count":15,"is_preprint":false},{"pmid":"33775676","id":"PMC_33775676","title":"Branching out the aerolysin, ETX/MTX-2 and Toxin_10 family of pore forming proteins.","date":"2021","source":"Journal of invertebrate pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33775676","citation_count":14,"is_preprint":false},{"pmid":"36449359","id":"PMC_36449359","title":"Discovery of a Highly Specific Anti-methotrexate (MTX) DNA Aptamer for Antibody-Independent MTX Detection.","date":"2022","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36449359","citation_count":14,"is_preprint":false},{"pmid":"30606816","id":"PMC_30606816","title":"MTHFR C677T polymorphism increases MTX sensitivity via the inhibition of S-adenosylmethionine and de novo purine synthesis.","date":"2019","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/30606816","citation_count":14,"is_preprint":false},{"pmid":"37352387","id":"PMC_37352387","title":"MTX-13, a Novel PTK7-Directed Antibody-Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors.","date":"2023","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37352387","citation_count":13,"is_preprint":false},{"pmid":"34421355","id":"PMC_34421355","title":"Genome-scale CRISPRa screening identifies MTX1 as a contributor for sorafenib resistance in hepatocellular carcinoma by augmenting autophagy.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34421355","citation_count":13,"is_preprint":false},{"pmid":"1616855","id":"PMC_1616855","title":"Monoclonal antibody targeting of methotrexate (MTX) against MTX-resistant tumour cell lines.","date":"1992","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/1616855","citation_count":13,"is_preprint":false},{"pmid":"37263756","id":"PMC_37263756","title":"Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX).","date":"2023","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37263756","citation_count":13,"is_preprint":false},{"pmid":"35887981","id":"PMC_35887981","title":"TNF-α Inhibitors in Combination with MTX Reduce Circulating Levels of Heparan Sulfate/Heparin and Endothelial Dysfunction Biomarkers (sVCAM-1, MCP-1, MMP-9 and ADMA) in Women with Rheumatoid Arthritis.","date":"2022","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35887981","citation_count":13,"is_preprint":false},{"pmid":"30905315","id":"PMC_30905315","title":"Adipocytes as lipid sensors of oleic acid transport through a functional Caco-2/HT29-MTX intestinal barrier.","date":"2019","source":"Adipocyte","url":"https://pubmed.ncbi.nlm.nih.gov/30905315","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56866,"output_tokens":1387,"usd":0.095701,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7543,"output_tokens":1578,"usd":0.038582,"stage2_stop_reason":"end_turn"},"total_usd":0.134283,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical MTX1 gene (Metaxin 1, also known as MTXN/MTX), which encodes a mitochondrial outer membrane protein.\n\nThe vast majority of papers are about:\n- HT29-MTX cells (a mucus-secreting cell line) - not the gene MTX1\n- Methotrexate (the drug, abbreviated MTX) - not the gene MTX1\n- Other toxins named MTX (Bacillus sphaericus mosquitocidal toxin, wasp toxins, mamba toxins) - not the gene MTX1\n\nOnly a few papers are actually about the MTX1 gene (Metaxin 1):\n\n**Paper [28]** (PMID: 8660965): \"Structure and organization of the human metaxin gene (MTX) and pseudogene\" - This is clearly about the MTX1 gene.\n\n**Paper [80]** (PMID: 21837367): \"Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age of onset in GBA-associated Parkinson's disease\" - This is about MTX1 gene variants.\n\n**Paper [96]** (PMID: 34421355): \"Genome-scale CRISPRa screening identifies MTX1 as a contributor for sorafenib resistance in hepatocellular carcinoma by augmenting autophagy\" - This is about MTX1 (Metaxin 1).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"The human MTX1 gene encodes a 317 amino acid mitochondrial protein. The predicted protein lacks an amino-terminal signal sequence and N-glycosylation sites but contains a putative transmembrane domain near its carboxy terminus. MTX1 is contiguous to THBS3 (sharing a common promoter region) and to the glucocerebrosidase pseudogene (psGBA), and a pseudogene for metaxin (psMTX) was identified within the GBA locus region. In liver, the pseudogene is not expressed.\",\n      \"method\": \"cDNA sequencing, genomic cloning, exon-intron mapping, Northern blot expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic and cDNA sequencing with expression analysis in a single focused study; structural features (transmembrane domain, lack of signal sequence) inferred from sequence prediction rather than experimental validation\",\n      \"pmids\": [\"8660965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MTX1 (Metaxin 1) overexpression promotes sorafenib resistance in hepatocellular carcinoma cells by augmenting autophagy. Mechanistically, MTX1 interacts with and inhibits CISD1 (CDGSH iron sulfur domain 1), a negative regulator of autophagy; loss of CISD1 activity leads to increased autophagy flux that confers drug resistance. MTX1 overexpression increased cell proliferation and decreased apoptosis upon sorafenib treatment both in vitro and in a subcutaneous xenograft model.\",\n      \"method\": \"CRISPRa genome-scale screening, co-immunoprecipitation (MTX1-CISD1 interaction), loss-of-function/gain-of-function experiments, in vitro cell proliferation/apoptosis assays, subcutaneous xenograft tumor model\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified by Co-IP, functional rescue experiments in vitro and in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34421355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The MTX1 c.184T>A (p.S63T) variant is found at high frequency in Ashkenazi GBA mutation carriers (allele frequency 0.67 vs 0.45 in non-carriers). Homozygosity for the MTX1 c.184A/A genotype is associated with significantly earlier age of motor symptom onset (5.1–5.9 years younger) in GBA-associated Parkinson's disease patients, suggesting that MTX1 variation on the allele trans to the GBA mutation can modify the clinical course of GBA-associated PD.\",\n      \"method\": \"Genotyping of MTX1 coding region in 600 Ashkenazi PD patients and 353 controls; statistical association analysis with age of onset\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic association study without functional mechanistic follow-up; no direct experiment on MTX1 protein function; single cohort\",\n      \"pmids\": [\"21837367\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTX1 (Metaxin 1) encodes a mitochondrial outer membrane protein with a C-terminal transmembrane domain and no amino-terminal signal sequence; it physically interacts with CISD1 (an autophagy negative regulator) and, when overexpressed, promotes autophagy-mediated sorafenib resistance in hepatocellular carcinoma, while a common coding variant (p.S63T) in linkage with GBA mutations modifies age of onset in Parkinson's disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTX1 (Metaxin 1) is a mitochondrial protein that influences autophagy and, through it, cell survival under stress [#0, #1]. It is a 317-residue protein that lacks an amino-terminal signal sequence but carries a putative transmembrane domain near its carboxy terminus, consistent with a tail-anchored topology in the mitochondrial outer membrane [#0]. Functionally, MTX1 physically interacts with and inhibits CISD1, a negative regulator of autophagy; this interaction relieves CISD1's restraint on autophagic flux, and MTX1 overexpression thereby augments autophagy to promote sorafenib resistance, increased proliferation, and reduced apoptosis in hepatocellular carcinoma cells and xenografts [#1]. The MTX1 gene resides at the GBA locus, and a coding variant (p.S63T) on the allele trans to GBA mutations is associated with earlier age of motor symptom onset in GBA-associated Parkinson's disease [#0, #2]. Beyond these findings, the biochemical basis of MTX1's transmembrane insertion and the structural detail of the MTX1-CISD1 interface have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of human MTX1 as a mitochondrial protein with a defined topology and genomic context, framing it as a tail-anchored outer-membrane candidate rather than a secreted or matrix protein.\",\n      \"evidence\": \"cDNA sequencing, genomic cloning, exon-intron mapping, and Northern blot in human tissues\",\n      \"pmids\": [\"8660965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transmembrane domain and lack of signal sequence inferred from sequence prediction, not experimentally validated\", \"Submitochondrial localization and membrane orientation not directly demonstrated\", \"No functional role assigned\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected MTX1 sequence variation to clinical phenotype, showing the p.S63T variant on the trans allele modifies age of onset in GBA-associated Parkinson's disease.\",\n      \"evidence\": \"Genotyping of MTX1 coding region in 600 Ashkenazi PD patients and 353 controls with age-of-onset association analysis\",\n      \"pmids\": [\"21837367\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Genetic association without functional mechanistic follow-up\", \"No direct experiment on MTX1 protein function\", \"Single cohort; linkage with GBA confounds attribution to MTX1\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a direct molecular mechanism for MTX1 in autophagy regulation, showing it inhibits CISD1 to drive autophagy-mediated drug resistance in cancer.\",\n      \"evidence\": \"CRISPRa genome-scale screen, MTX1-CISD1 co-immunoprecipitation, gain/loss-of-function assays, and subcutaneous xenograft model in hepatocellular carcinoma\",\n      \"pmids\": [\"34421355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction shown by Co-IP without structural definition of the binding interface\", \"Mechanism by which CISD1 inhibition increases autophagy flux not resolved at the molecular level\", \"Demonstrated in HCC context; generality across tissues unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTX1's outer-membrane topology relates to its CISD1-dependent autophagy function, and whether the Parkinson's-associated variant alters this activity, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the MTX1-CISD1 complex\", \"No link established between the p.S63T variant and any biochemical or autophagy phenotype\", \"Membrane insertion mechanism not experimentally characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CISD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}