{"gene":"MTX2","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2020,"finding":"Loss of MTX2 in patient fibroblasts leads to loss of Metaxin-1 (MTX1) protein and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment; MTX2-null cells show resistance to induced apoptosis, increased cell senescence, increased mitophagy, and reduced proliferation. Secondary nuclear morphological defects occur in both MTX2-mutant human fibroblasts and mtx-2-depleted C. elegans, establishing a link between mitochondrial composition/function and nuclear morphology.","method":"Patient primary fibroblast analysis (loss-of-function), C. elegans mtx-2 depletion, oxidative phosphorylation assays, apoptosis resistance assays, mitophagy quantification","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in patient fibroblasts and C. elegans model, replicated across two systems","pmids":["32917887"],"is_preprint":false},{"year":2021,"finding":"AREL1 E3 ubiquitin ligase ubiquitinates MTX2, promoting its proteasomal degradation; AREL1 interacts with the carboxyl-terminal domain of MTX2, while the amino-terminal domain of MTX2 interacts with MTX1. AREL1-mediated degradation of MTX2 inhibits TNF-induced necroptosis, whereas MTX2 together with MTX1 enhances necroptosis.","method":"Co-immunoprecipitation, domain mapping, AREL1 catalytic mutant (C790A) analysis, AREL1 knockdown, overexpression","journal":"Experimental and Therapeutic Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping and catalytic mutant controls, single lab","pmids":["34584540"],"is_preprint":false},{"year":2024,"finding":"MTX2 deficiency in podocytes leads to dysfunction of the Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging (MIB) complex, causing abnormal mitochondrial cristae morphology, defects in respiratory complexes I and III, increased ROS, and impaired podocyte adhesion, migration, and endocytosis. Conditional podocyte-specific Mtx2 KO mice develop microalbuminuria and glomerular abnormalities.","method":"Conditional podocyte-specific Mtx2 knockout mice, in vitro podocyte loss-of-function and rescue by MTX2 overexpression, mitochondrial complex activity assays, ROS measurement, western blotting for MIB complex components","journal":"International Journal of Biological Sciences","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined cellular phenotype, in vitro rescue experiment, multiple biochemical readouts","pmids":["38250156"],"is_preprint":false},{"year":2025,"finding":"The TOM37 domain of MTX2 directly interacts with PKM2 to promote PKM2 tetramerization, thereby enhancing glycolytic flux. Cardiomyocyte-specific Mtx2 deletion leads to accumulation of dimeric (less active) PKM2 after ischemia/reperfusion, impaired oxidative phosphorylation and glycolysis, and aggravated cardiac injury; pharmacological PKM2 tetramerization (TEPP-46) rescues these defects.","method":"Cardiomyocyte-specific Mtx2 knockout mice, adenovirus-mediated overexpression, mass spectrometry, co-immunoprecipitation, Seahorse metabolic analysis, RNA sequencing, pharmacological rescue","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 — domain-specific interaction identified by MS and Co-IP, loss/gain-of-function in vivo, pharmacological rescue, multiple orthogonal methods","pmids":["40585998"],"is_preprint":false},{"year":2026,"finding":"USP10 deubiquitinates K48-linked ubiquitination of MTX2 at lysine-93 (K93), stabilizing MTX2 protein. USP10 loss leads to MTX2 degradation, mitochondrial dysfunction, release of mitochondrial DNA into the cytosol, and activation of the cGAS-STING signaling pathway after myocardial infarction; the MTX2-K93R mutation rescues the exacerbated cardiac injury caused by USP10 loss.","method":"Immunoprecipitation mass spectrometry, ubiquitination assays, mutagenesis (K93R), USP10 knockdown/KO mice, neonatal rat cardiomyocyte culture","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 1–2 — site-specific mutagenesis identifies K93, IP-MS, ubiquitination assays, rescue experiment, in vivo model","pmids":["41705350"],"is_preprint":false},{"year":2024,"finding":"mtx-2-deficient C. elegans display rougher and less elastic cuticle (measured by AFM), abnormal mitochondrial morphology, delayed development, decreased pharyngeal pumping, and significantly reduced mitochondrial respiratory capacity; transcriptomic analysis identified perturbations in aging, TOR, and WNT-signaling pathways.","method":"Atomic force microscopy, oxygen consumption rate analysis, transcriptomics, phenotypic characterization of mtx-2 C. elegans knockdown","journal":"Communications Biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in C. elegans model, single lab","pmids":["39462037"],"is_preprint":false},{"year":2025,"finding":"In Xenopus laevis, knockdown of mtx2 causes reduced head size, hypoplastic cranial cartilage, disrupted neural crest and chondrogenic marker expression, decreased cell proliferation, and increased apoptosis. Domain-deletion rescue experiments show the C-terminal GST-like domain of Mtx2 is essential for craniofacial morphogenesis, while the N-terminal GST-like domain is dispensable.","method":"Morpholino knockdown in Xenopus, deletion-rescue experiments with N- and C-terminal domain deletions, marker gene expression analysis, proliferation and apoptosis assays","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — domain-specific rescue experiments with phenotypic readouts, single lab","pmids":["40967033"],"is_preprint":false},{"year":2025,"finding":"In Drosophila, Mtx2 null mutants exhibit pupal lethality rescued by either Drosophila or human Mtx2, confirming functional conservation. Muscle-specific conditional knockout reveals Mtx2 is required for myofibril assembly, myogenic protein levels, and mitochondrial structural/functional integrity. Mtx2 deficiency affects beta-barrel protein biogenesis specifically in pupa but not larva, demonstrating stage-specific regulation of mitochondrial proteostasis.","method":"Drosophila Mtx2 null mutants, tissue-specific conditional KO, human/Drosophila Mtx2 rescue, myofibril imaging, mitochondrial functional assays, protein biogenesis analysis","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with tissue-specific rescue in an established model organism, multiple readouts; preprint","pmids":["bio_10.1101_2025.05.22.655489"],"is_preprint":true}],"current_model":"MTX2 (Metaxin-2) is an outer mitochondrial membrane protein that forms a complex with Metaxin-1 (MTX1) and is required for mitochondrial protein import (including beta-barrel protein biogenesis), maintenance of mitochondrial network integrity, cristae morphology via the Sam50-CHCHD3-Mitofilin (MIB) axis, and oxidative phosphorylation; it directly interacts with PKM2 via its TOM37 domain to promote PKM2 tetramerization and glycolytic flux, participates in TNF-induced necroptosis signaling, and is regulated post-translationally by AREL1-mediated ubiquitin-dependent degradation and USP10-mediated deubiquitination at K93, with its loss causing nuclear morphology defects, premature aging phenotypes, podocyte injury, and cardiac injury."},"narrative":{"teleology":[{"year":2020,"claim":"Establishing MTX2 as essential for mitochondrial and nuclear integrity: patient fibroblasts and C. elegans depletion revealed that MTX2 loss destabilizes MTX1, fragments the mitochondrial network, impairs oxidative phosphorylation, induces senescence and mitophagy, and secondarily disrupts nuclear morphology—linking outer mitochondrial membrane composition to nuclear envelope homeostasis.","evidence":"Patient fibroblast analysis with MTX2 loss-of-function, C. elegans mtx-2 depletion, oxidative phosphorylation assays, apoptosis resistance and mitophagy quantification","pmids":["32917887"],"confidence":"High","gaps":["Mechanism by which mitochondrial dysfunction propagates to nuclear envelope defects is undefined","Whether MTX2 directly participates in protein import or acts indirectly through MTX1 stabilization was not resolved","No specific mitochondrial import substrates identified"]},{"year":2021,"claim":"Identifying post-translational regulation of MTX2: AREL1 was shown to ubiquitinate MTX2 at its C-terminal domain for proteasomal degradation, and this degradation suppresses TNF-induced necroptosis, placing MTX2 turnover upstream of necroptotic signaling.","evidence":"Reciprocal co-immunoprecipitation, domain mapping, AREL1 catalytic mutant (C790A), AREL1 knockdown and overexpression","pmids":["34584540"],"confidence":"Medium","gaps":["Specific ubiquitination sites on MTX2 targeted by AREL1 were not mapped","Mechanism connecting MTX2/MTX1 to necroptosis execution machinery is unknown","Single-lab finding not independently replicated"]},{"year":2024,"claim":"Defining the cristae-organizing role of MTX2: podocyte-specific Mtx2 knockout revealed that MTX2 maintains the Sam50-CHCHD3-Mitofilin (MIB) complex, and its loss causes cristae disorganization, respiratory complex I/III deficiency, increased ROS, and podocyte functional impairment leading to glomerular disease in vivo.","evidence":"Conditional podocyte-specific Mtx2 KO mice, in vitro rescue by MTX2 overexpression, mitochondrial complex activity assays, ROS measurement, western blotting for MIB components","pmids":["38250156"],"confidence":"High","gaps":["Whether MTX2 directly contacts Sam50 or acts through MTX1 to stabilize the MIB complex is unresolved","The structural basis of MTX2-MIB interaction is unknown"]},{"year":2024,"claim":"Connecting MTX2 to organismal aging pathways: C. elegans mtx-2 deficiency caused cuticle abnormalities, reduced mitochondrial respiration, and transcriptomic perturbations in aging, TOR, and WNT signaling, extending the functional scope of MTX2 beyond cell-autonomous mitochondrial defects.","evidence":"Atomic force microscopy, oxygen consumption rate analysis, transcriptomics in mtx-2-deficient C. elegans","pmids":["39462037"],"confidence":"Medium","gaps":["Whether TOR and WNT pathway changes are direct or secondary to mitochondrial dysfunction is unknown","Causal relationship between cuticle defects and mitochondrial impairment not established"]},{"year":2025,"claim":"Revealing a direct metabolic effector function: the TOM37 domain of MTX2 was found to directly bind PKM2 and promote its tetramerization, enhancing glycolytic flux; cardiomyocyte-specific Mtx2 deletion impaired both glycolysis and oxidative phosphorylation after ischemia/reperfusion, and pharmacological PKM2 tetramerization rescued the injury phenotype.","evidence":"Cardiomyocyte-specific Mtx2 KO mice, mass spectrometry, co-immunoprecipitation, Seahorse metabolic analysis, TEPP-46 pharmacological rescue","pmids":["40585998"],"confidence":"High","gaps":["Whether PKM2 binding is constitutive or regulated by stress/metabolic state is unclear","Other TOM37 domain interaction partners have not been systematically catalogued"]},{"year":2025,"claim":"Establishing a developmental requirement via the C-terminal GST-like domain: Xenopus mtx2 knockdown caused craniofacial defects through impaired neural crest cell proliferation, and domain-deletion rescue showed the C-terminal GST-like domain is essential while the N-terminal GST-like domain is dispensable for this function.","evidence":"Morpholino knockdown in Xenopus, domain-deletion rescue constructs, marker gene expression, proliferation and apoptosis assays","pmids":["40967033"],"confidence":"Medium","gaps":["The molecular activity of the C-terminal GST-like domain (enzymatic vs. structural) is not defined","Whether craniofacial defects stem from mitochondrial dysfunction or a separate MTX2 function is unresolved"]},{"year":2026,"claim":"Pinpointing a site-specific deubiquitination mechanism: USP10 was identified as the deubiquitinase that removes K48-linked ubiquitin from MTX2 at K93, stabilizing MTX2; USP10 loss causes MTX2 degradation, mitochondrial DNA release, and cGAS-STING activation, with the K93R mutation fully rescuing the cardiac injury phenotype.","evidence":"Immunoprecipitation mass spectrometry, ubiquitination assays, K93R mutagenesis, USP10 KO mice, neonatal rat cardiomyocyte culture","pmids":["41705350"],"confidence":"High","gaps":["Whether K93 is the sole regulatory ubiquitination site or one of several is not resolved","The E3 ligase responsible for K93 ubiquitination (whether AREL1 or another) is not identified in this study","Mechanism linking MTX2 degradation to mitochondrial DNA release remains undefined"]},{"year":null,"claim":"Key unresolved questions include the structural basis of MTX2 integration into the outer mitochondrial membrane, the identity of specific protein import substrates that depend on MTX2, whether the AREL1-targeted and USP10-targeted ubiquitination events converge on the same site, and the mechanism by which mitochondrial dysfunction secondary to MTX2 loss causes nuclear envelope defects.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of MTX2 or its complexes exists","Specific mitochondrial import substrates dependent on MTX2 have not been identified","The signaling pathway from mitochondrial dysfunction to nuclear morphology changes is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,3,4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,2]}],"complexes":["MTX1-MTX2 complex","Sam50-CHCHD3-Mitofilin (MIB) complex"],"partners":["MTX1","AREL1","USP10","PKM2","SAM50","CHCHD3"],"other_free_text":[]},"mechanistic_narrative":"MTX2 (Metaxin-2) is an outer mitochondrial membrane protein essential for mitochondrial protein import, cristae architecture, oxidative phosphorylation, and cellular homeostasis across metazoans. MTX2 forms a complex with MTX1 through its N-terminal domain and maintains the Sam50-CHCHD3-Mitofilin (MIB) complex required for normal cristae morphology and respiratory complex I/III function; its loss causes mitochondrial fragmentation, increased ROS, impaired oxidative phosphorylation, increased mitophagy, and secondary nuclear morphology defects [PMID:32917887, PMID:38250156]. The TOM37 domain of MTX2 directly binds PKM2 to promote its tetramerization and enhance glycolytic flux, while MTX2 protein stability is regulated by AREL1-mediated K48-linked ubiquitination and USP10-mediated deubiquitination at K93, with USP10 loss triggering MTX2 degradation, mitochondrial DNA release, and cGAS-STING pathway activation [PMID:40585998, PMID:34584540, PMID:41705350]. Biallelic loss-of-function mutations in MTX2 cause a premature aging syndrome with mitochondrial dysfunction and nuclear envelope abnormalities in humans [PMID:32917887]."},"prefetch_data":{"uniprot":{"accession":"O75431","full_name":"Metaxin-2","aliases":["Mitochondrial outer membrane import complex protein 2"],"length_aa":263,"mass_kda":29.8,"function":"Involved in transport of proteins into the mitochondrion","subcellular_location":"Mitochondrion outer membrane; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O75431/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTX2","classification":"Not Classified","n_dependent_lines":92,"n_total_lines":1208,"dependency_fraction":0.076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX39B","stoichiometry":0.2},{"gene":"DNAJC11","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MTX2","total_profiled":1310},"omim":[{"mim_id":"619127","title":"MANDIBULOACRAL DYSPLASIA PROGEROID SYNDROME; MDPS","url":"https://www.omim.org/entry/619127"},{"mim_id":"616731","title":"NIMA-RELATED KINASE 5; NEK5","url":"https://www.omim.org/entry/616731"},{"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":"613681","title":"CHROMOSOME 2q31.1 DUPLICATION SYNDROME","url":"https://www.omim.org/entry/613681"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTX2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O75431","domains":[{"cath_id":"3.40.30.10","chopping":"2-94","consensus_level":"medium","plddt":89.208,"start":2,"end":94},{"cath_id":"1.20.1050.10","chopping":"104-256","consensus_level":"medium","plddt":96.4442,"start":104,"end":256}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75431","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75431-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75431-F1-predicted_aligned_error_v6.png","plddt_mean":92.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTX2","jax_strain_url":"https://www.jax.org/strain/search?query=MTX2"},"sequence":{"accession":"O75431","fasta_url":"https://rest.uniprot.org/uniprotkb/O75431.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75431/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75431"}},"corpus_meta":[{"pmid":"32917887","id":"PMC_32917887","title":"Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32917887","citation_count":53,"is_preprint":false},{"pmid":"15765511","id":"PMC_15765511","title":"T-box gene eomesodermin and the homeobox-containing Mix/Bix gene mtx2 regulate epiboly movements in the zebrafish.","date":"2005","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/15765511","citation_count":42,"is_preprint":false},{"pmid":"7778123","id":"PMC_7778123","title":"Binding of muscarinic toxins MTx1 and MTx2 from the venom of the green mamba Dendroaspis angusticeps to cloned human muscarinic cholinoceptors.","date":"1995","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/7778123","citation_count":31,"is_preprint":false},{"pmid":"29150505","id":"PMC_29150505","title":"Cry64Ba and Cry64Ca, Two ETX/MTX2-Type Bacillus thuringiensis Insecticidal Proteins Active against Hemipteran Pests.","date":"2018","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29150505","citation_count":27,"is_preprint":false},{"pmid":"18154948","id":"PMC_18154948","title":"Mtx2 directs zebrafish morphogenetic movements during epiboly by regulating microfilament formation.","date":"2007","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18154948","citation_count":25,"is_preprint":false},{"pmid":"7672121","id":"PMC_7672121","title":"A particularly labile Asp-Pro bond in the green mamba muscarinic toxin MTX2. Effect of protein conformation on the rate of cleavage.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7672121","citation_count":23,"is_preprint":false},{"pmid":"27235983","id":"PMC_27235983","title":"The sequence, structural, and functional diversity within a protein family and implications for specificity and safety: The case for ETX_MTX2 insecticidal proteins.","date":"2016","source":"Journal of invertebrate pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27235983","citation_count":23,"is_preprint":false},{"pmid":"8662969","id":"PMC_8662969","title":"Unusual amino acid determinants of host range in the Mtx2 family of mosquitocidal toxins.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8662969","citation_count":19,"is_preprint":false},{"pmid":"33869216","id":"PMC_33869216","title":"LncRNA MTX2-6 Suppresses Cell Proliferation by Acting as ceRNA of miR-574-5p to Accumulate SMAD4 in Esophageal Squamous Cell Carcinoma.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33869216","citation_count":12,"is_preprint":false},{"pmid":"38250156","id":"PMC_38250156","title":"Loss of MTX2 causes mitochondrial dysfunction, podocyte injury, nephrotic proteinuria and glomerulopathy in mice and patients.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38250156","citation_count":11,"is_preprint":false},{"pmid":"19082531","id":"PMC_19082531","title":"Bacillus sphaericus Mtx1 and Mtx2 toxins co-expressed in Escherichia coli are synergistic against Aedes aegypti larvae.","date":"2008","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/19082531","citation_count":10,"is_preprint":false},{"pmid":"36269149","id":"PMC_36269149","title":"A novel MTX2 gene splice site variant resulting in exon skipping, causing the recently described mandibuloacral dysplasia progeroid syndrome.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36269149","citation_count":9,"is_preprint":false},{"pmid":"36074780","id":"PMC_36074780","title":"Safety assessment of Mpp75Aa1.1, a new ETX_MTX2 protein from Brevibacillus laterosporus that controls western corn rootworm.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36074780","citation_count":6,"is_preprint":false},{"pmid":"20411263","id":"PMC_20411263","title":"Production and characterization of N- and C-terminally truncated Mtx2: a mosquitocidal toxin from Bacillus sphaericus.","date":"2010","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20411263","citation_count":6,"is_preprint":false},{"pmid":"34584540","id":"PMC_34584540","title":"AREL1 E3 ubiquitin ligase inhibits TNF-induced necroptosis via the ubiquitination of MTX2.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34584540","citation_count":6,"is_preprint":false},{"pmid":"40585998","id":"PMC_40585998","title":"MTX2 facilitates PKM2 tetramerization to promote cardiac glucose metabolism and protects the heart against ischemia/reperfusion injury.","date":"2025","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/40585998","citation_count":4,"is_preprint":false},{"pmid":"37341620","id":"PMC_37341620","title":"Structural insight into Bacillus thuringiensis Sip1Ab reveals its similarity to ETX_MTX2 family beta-pore-forming toxin.","date":"2023","source":"Pest management science","url":"https://pubmed.ncbi.nlm.nih.gov/37341620","citation_count":2,"is_preprint":false},{"pmid":"38544690","id":"PMC_38544690","title":"Case report: A novel splice-site mutation of MTX2 gene caused mandibuloacral dysplasia progeroid syndrome: the first report from China and literature review.","date":"2024","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/38544690","citation_count":2,"is_preprint":false},{"pmid":"34137359","id":"PMC_34137359","title":"Production of Lysinibacillus sphaericus Mosquitocidal Protein Mtx2 from Bacillus subtilis as a Secretory Protein.","date":"2021","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/34137359","citation_count":1,"is_preprint":false},{"pmid":"39462037","id":"PMC_39462037","title":"Validation of metaxin-2 deficient C. elegans as a model for MandibuloAcral Dysplasia associated to mtx-2 (MADaM) syndrome.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39462037","citation_count":1,"is_preprint":false},{"pmid":"41705350","id":"PMC_41705350","title":"USP10 Deubiquitinates MTX2 to Suppress cGAS-STING Signaling in MI.","date":"2026","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/41705350","citation_count":0,"is_preprint":false},{"pmid":"40967033","id":"PMC_40967033","title":"Mtx2 requirement for craniofacial morphogenesis with implications for mandibuloacral dysplasia.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/40967033","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.22.655489","title":"<i>Drosophila</i> Metaxin-2 controls beta-barrel protein biogenesis and muscle growth in a stage-dependent fashion","date":"2025-05-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.22.655489","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12435,"output_tokens":2367,"usd":0.036405},"stage2":{"model":"claude-opus-4-6","input_tokens":5641,"output_tokens":2609,"usd":0.140145},"total_usd":0.17655,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of MTX2 in patient fibroblasts leads to loss of Metaxin-1 (MTX1) protein and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment; MTX2-null cells show resistance to induced apoptosis, increased cell senescence, increased mitophagy, and reduced proliferation. Secondary nuclear morphological defects occur in both MTX2-mutant human fibroblasts and mtx-2-depleted C. elegans, establishing a link between mitochondrial composition/function and nuclear morphology.\",\n      \"method\": \"Patient primary fibroblast analysis (loss-of-function), C. elegans mtx-2 depletion, oxidative phosphorylation assays, apoptosis resistance assays, mitophagy quantification\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in patient fibroblasts and C. elegans model, replicated across two systems\",\n      \"pmids\": [\"32917887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AREL1 E3 ubiquitin ligase ubiquitinates MTX2, promoting its proteasomal degradation; AREL1 interacts with the carboxyl-terminal domain of MTX2, while the amino-terminal domain of MTX2 interacts with MTX1. AREL1-mediated degradation of MTX2 inhibits TNF-induced necroptosis, whereas MTX2 together with MTX1 enhances necroptosis.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, AREL1 catalytic mutant (C790A) analysis, AREL1 knockdown, overexpression\",\n      \"journal\": \"Experimental and Therapeutic Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping and catalytic mutant controls, single lab\",\n      \"pmids\": [\"34584540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MTX2 deficiency in podocytes leads to dysfunction of the Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging (MIB) complex, causing abnormal mitochondrial cristae morphology, defects in respiratory complexes I and III, increased ROS, and impaired podocyte adhesion, migration, and endocytosis. Conditional podocyte-specific Mtx2 KO mice develop microalbuminuria and glomerular abnormalities.\",\n      \"method\": \"Conditional podocyte-specific Mtx2 knockout mice, in vitro podocyte loss-of-function and rescue by MTX2 overexpression, mitochondrial complex activity assays, ROS measurement, western blotting for MIB complex components\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined cellular phenotype, in vitro rescue experiment, multiple biochemical readouts\",\n      \"pmids\": [\"38250156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The TOM37 domain of MTX2 directly interacts with PKM2 to promote PKM2 tetramerization, thereby enhancing glycolytic flux. Cardiomyocyte-specific Mtx2 deletion leads to accumulation of dimeric (less active) PKM2 after ischemia/reperfusion, impaired oxidative phosphorylation and glycolysis, and aggravated cardiac injury; pharmacological PKM2 tetramerization (TEPP-46) rescues these defects.\",\n      \"method\": \"Cardiomyocyte-specific Mtx2 knockout mice, adenovirus-mediated overexpression, mass spectrometry, co-immunoprecipitation, Seahorse metabolic analysis, RNA sequencing, pharmacological rescue\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain-specific interaction identified by MS and Co-IP, loss/gain-of-function in vivo, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40585998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP10 deubiquitinates K48-linked ubiquitination of MTX2 at lysine-93 (K93), stabilizing MTX2 protein. USP10 loss leads to MTX2 degradation, mitochondrial dysfunction, release of mitochondrial DNA into the cytosol, and activation of the cGAS-STING signaling pathway after myocardial infarction; the MTX2-K93R mutation rescues the exacerbated cardiac injury caused by USP10 loss.\",\n      \"method\": \"Immunoprecipitation mass spectrometry, ubiquitination assays, mutagenesis (K93R), USP10 knockdown/KO mice, neonatal rat cardiomyocyte culture\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific mutagenesis identifies K93, IP-MS, ubiquitination assays, rescue experiment, in vivo model\",\n      \"pmids\": [\"41705350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"mtx-2-deficient C. elegans display rougher and less elastic cuticle (measured by AFM), abnormal mitochondrial morphology, delayed development, decreased pharyngeal pumping, and significantly reduced mitochondrial respiratory capacity; transcriptomic analysis identified perturbations in aging, TOR, and WNT-signaling pathways.\",\n      \"method\": \"Atomic force microscopy, oxygen consumption rate analysis, transcriptomics, phenotypic characterization of mtx-2 C. elegans knockdown\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in C. elegans model, single lab\",\n      \"pmids\": [\"39462037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Xenopus laevis, knockdown of mtx2 causes reduced head size, hypoplastic cranial cartilage, disrupted neural crest and chondrogenic marker expression, decreased cell proliferation, and increased apoptosis. Domain-deletion rescue experiments show the C-terminal GST-like domain of Mtx2 is essential for craniofacial morphogenesis, while the N-terminal GST-like domain is dispensable.\",\n      \"method\": \"Morpholino knockdown in Xenopus, deletion-rescue experiments with N- and C-terminal domain deletions, marker gene expression analysis, proliferation and apoptosis assays\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific rescue experiments with phenotypic readouts, single lab\",\n      \"pmids\": [\"40967033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, Mtx2 null mutants exhibit pupal lethality rescued by either Drosophila or human Mtx2, confirming functional conservation. Muscle-specific conditional knockout reveals Mtx2 is required for myofibril assembly, myogenic protein levels, and mitochondrial structural/functional integrity. Mtx2 deficiency affects beta-barrel protein biogenesis specifically in pupa but not larva, demonstrating stage-specific regulation of mitochondrial proteostasis.\",\n      \"method\": \"Drosophila Mtx2 null mutants, tissue-specific conditional KO, human/Drosophila Mtx2 rescue, myofibril imaging, mitochondrial functional assays, protein biogenesis analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with tissue-specific rescue in an established model organism, multiple readouts; preprint\",\n      \"pmids\": [\"bio_10.1101_2025.05.22.655489\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MTX2 (Metaxin-2) is an outer mitochondrial membrane protein that forms a complex with Metaxin-1 (MTX1) and is required for mitochondrial protein import (including beta-barrel protein biogenesis), maintenance of mitochondrial network integrity, cristae morphology via the Sam50-CHCHD3-Mitofilin (MIB) axis, and oxidative phosphorylation; it directly interacts with PKM2 via its TOM37 domain to promote PKM2 tetramerization and glycolytic flux, participates in TNF-induced necroptosis signaling, and is regulated post-translationally by AREL1-mediated ubiquitin-dependent degradation and USP10-mediated deubiquitination at K93, with its loss causing nuclear morphology defects, premature aging phenotypes, podocyte injury, and cardiac injury.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MTX2 (Metaxin-2) is an outer mitochondrial membrane protein essential for mitochondrial protein import, cristae architecture, oxidative phosphorylation, and cellular homeostasis across metazoans. MTX2 forms a complex with MTX1 through its N-terminal domain and maintains the Sam50-CHCHD3-Mitofilin (MIB) complex required for normal cristae morphology and respiratory complex I/III function; its loss causes mitochondrial fragmentation, increased ROS, impaired oxidative phosphorylation, increased mitophagy, and secondary nuclear morphology defects [PMID:32917887, PMID:38250156]. The TOM37 domain of MTX2 directly binds PKM2 to promote its tetramerization and enhance glycolytic flux, while MTX2 protein stability is regulated by AREL1-mediated K48-linked ubiquitination and USP10-mediated deubiquitination at K93, with USP10 loss triggering MTX2 degradation, mitochondrial DNA release, and cGAS-STING pathway activation [PMID:40585998, PMID:34584540, PMID:41705350]. Biallelic loss-of-function mutations in MTX2 cause a premature aging syndrome with mitochondrial dysfunction and nuclear envelope abnormalities in humans [PMID:32917887].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing MTX2 as essential for mitochondrial and nuclear integrity: patient fibroblasts and C. elegans depletion revealed that MTX2 loss destabilizes MTX1, fragments the mitochondrial network, impairs oxidative phosphorylation, induces senescence and mitophagy, and secondarily disrupts nuclear morphology—linking outer mitochondrial membrane composition to nuclear envelope homeostasis.\",\n      \"evidence\": \"Patient fibroblast analysis with MTX2 loss-of-function, C. elegans mtx-2 depletion, oxidative phosphorylation assays, apoptosis resistance and mitophagy quantification\",\n      \"pmids\": [\"32917887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which mitochondrial dysfunction propagates to nuclear envelope defects is undefined\",\n        \"Whether MTX2 directly participates in protein import or acts indirectly through MTX1 stabilization was not resolved\",\n        \"No specific mitochondrial import substrates identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying post-translational regulation of MTX2: AREL1 was shown to ubiquitinate MTX2 at its C-terminal domain for proteasomal degradation, and this degradation suppresses TNF-induced necroptosis, placing MTX2 turnover upstream of necroptotic signaling.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, domain mapping, AREL1 catalytic mutant (C790A), AREL1 knockdown and overexpression\",\n      \"pmids\": [\"34584540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific ubiquitination sites on MTX2 targeted by AREL1 were not mapped\",\n        \"Mechanism connecting MTX2/MTX1 to necroptosis execution machinery is unknown\",\n        \"Single-lab finding not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining the cristae-organizing role of MTX2: podocyte-specific Mtx2 knockout revealed that MTX2 maintains the Sam50-CHCHD3-Mitofilin (MIB) complex, and its loss causes cristae disorganization, respiratory complex I/III deficiency, increased ROS, and podocyte functional impairment leading to glomerular disease in vivo.\",\n      \"evidence\": \"Conditional podocyte-specific Mtx2 KO mice, in vitro rescue by MTX2 overexpression, mitochondrial complex activity assays, ROS measurement, western blotting for MIB components\",\n      \"pmids\": [\"38250156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MTX2 directly contacts Sam50 or acts through MTX1 to stabilize the MIB complex is unresolved\",\n        \"The structural basis of MTX2-MIB interaction is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connecting MTX2 to organismal aging pathways: C. elegans mtx-2 deficiency caused cuticle abnormalities, reduced mitochondrial respiration, and transcriptomic perturbations in aging, TOR, and WNT signaling, extending the functional scope of MTX2 beyond cell-autonomous mitochondrial defects.\",\n      \"evidence\": \"Atomic force microscopy, oxygen consumption rate analysis, transcriptomics in mtx-2-deficient C. elegans\",\n      \"pmids\": [\"39462037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TOR and WNT pathway changes are direct or secondary to mitochondrial dysfunction is unknown\",\n        \"Causal relationship between cuticle defects and mitochondrial impairment not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing a direct metabolic effector function: the TOM37 domain of MTX2 was found to directly bind PKM2 and promote its tetramerization, enhancing glycolytic flux; cardiomyocyte-specific Mtx2 deletion impaired both glycolysis and oxidative phosphorylation after ischemia/reperfusion, and pharmacological PKM2 tetramerization rescued the injury phenotype.\",\n      \"evidence\": \"Cardiomyocyte-specific Mtx2 KO mice, mass spectrometry, co-immunoprecipitation, Seahorse metabolic analysis, TEPP-46 pharmacological rescue\",\n      \"pmids\": [\"40585998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PKM2 binding is constitutive or regulated by stress/metabolic state is unclear\",\n        \"Other TOM37 domain interaction partners have not been systematically catalogued\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing a developmental requirement via the C-terminal GST-like domain: Xenopus mtx2 knockdown caused craniofacial defects through impaired neural crest cell proliferation, and domain-deletion rescue showed the C-terminal GST-like domain is essential while the N-terminal GST-like domain is dispensable for this function.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus, domain-deletion rescue constructs, marker gene expression, proliferation and apoptosis assays\",\n      \"pmids\": [\"40967033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular activity of the C-terminal GST-like domain (enzymatic vs. structural) is not defined\",\n        \"Whether craniofacial defects stem from mitochondrial dysfunction or a separate MTX2 function is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Pinpointing a site-specific deubiquitination mechanism: USP10 was identified as the deubiquitinase that removes K48-linked ubiquitin from MTX2 at K93, stabilizing MTX2; USP10 loss causes MTX2 degradation, mitochondrial DNA release, and cGAS-STING activation, with the K93R mutation fully rescuing the cardiac injury phenotype.\",\n      \"evidence\": \"Immunoprecipitation mass spectrometry, ubiquitination assays, K93R mutagenesis, USP10 KO mice, neonatal rat cardiomyocyte culture\",\n      \"pmids\": [\"41705350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether K93 is the sole regulatory ubiquitination site or one of several is not resolved\",\n        \"The E3 ligase responsible for K93 ubiquitination (whether AREL1 or another) is not identified in this study\",\n        \"Mechanism linking MTX2 degradation to mitochondrial DNA release remains undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of MTX2 integration into the outer mitochondrial membrane, the identity of specific protein import substrates that depend on MTX2, whether the AREL1-targeted and USP10-targeted ubiquitination events converge on the same site, and the mechanism by which mitochondrial dysfunction secondary to MTX2 loss causes nuclear envelope defects.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of MTX2 or its complexes exists\",\n        \"Specific mitochondrial import substrates dependent on MTX2 have not been identified\",\n        \"The signaling pathway from mitochondrial dysfunction to nuclear morphology changes is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"MTX1-MTX2 complex\",\n      \"Sam50-CHCHD3-Mitofilin (MIB) complex\"\n    ],\n    \"partners\": [\n      \"MTX1\",\n      \"AREL1\",\n      \"USP10\",\n      \"PKM2\",\n      \"SAM50\",\n      \"CHCHD3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}