{"gene":"TMEM223","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2021,"finding":"TMEM223 was identified as a ribosome-associated protein in human mitochondria that stimulates the translation of COX1 mRNA and is a constituent of early COX1 assembly intermediates, linking mitochondrial translation to complex IV biogenesis.","method":"Ribosome purification from mitochondria, interactome analysis, functional knockdown with phenotypic readout (COX1 translation and complex IV assembly intermediates)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal purification, multiple orthogonal methods (interactome, assembly intermediate profiling, translation assay), single lab but comprehensive","pmids":["34969438"],"is_preprint":false},{"year":2020,"finding":"TMEM223 (and TMEM186) are mitochondrially localized proteins in human cells, belonging to the TMEM70/TMEM186/TMEM223 protein family that co-occurs only in species with OXPHOS complexes, suggesting a conserved role in OXPHOS assembly.","method":"Subcellular localization experiments (mitochondrial localization confirmed), evolutionary coevolution analysis","journal":"Biochimica et biophysica acta. Bioenergetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment combined with evolutionary analysis, single lab","pmids":["32275929"],"is_preprint":false},{"year":2018,"finding":"Yeast Mrx15 (ortholog of TMEM223) interacts with the large mitochondrial ribosomal subunit via a soluble C-terminal domain, contacts mitochondrial translation products during their synthesis, and plays an overlapping role with ribosome receptor Mba1 in cotranslational membrane protein insertion.","method":"Mass spectrometry-based interaction screen, ribosome co-purification, genetic epistasis (double mutant analysis)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interaction mapping plus genetic epistasis, replicated with multiple approaches in single study, consistent with human TMEM223 data","pmids":["30091672"],"is_preprint":false},{"year":2018,"finding":"Yeast Mrx15 (ortholog of TMEM223) genetically interacts with regulators of the i-AAA protease (Mgr1 and Mgr3); simultaneous absence of Mrx15 and Mgr1/Mgr3 provokes respiratory deficiency, suggesting functional coupling between mitochondrial membrane protein insertion and AAA-protease quality control.","method":"Genetic epistasis (double/triple deletion mutants), respiratory growth assay, proteotoxic stress assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in yeast, single lab, multiple mutant combinations tested","pmids":["30336542"],"is_preprint":false},{"year":2021,"finding":"Mrx15 (yeast ortholog of TMEM223) is broadly conserved in eukaryotes and is a mitochondrial ribosome-interacting protein implicated in membrane protein targeting, functionally nonredundant with the mitochondrial SRP system.","method":"Phylogenetic/comparative genomics with experimental confirmation of mitochondrial localization in model organisms","journal":"Molecular biology and evolution","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily comparative/evolutionary analysis; direct functional experiments are in other organisms and not specifically on TMEM223","pmids":["33837778"],"is_preprint":false},{"year":2019,"finding":"TMEM223 interacts with the CaV2.2 voltage-gated Ca2+ channel (domain IV), lowers average current density, accelerates cumulative current inactivation kinetics, and slows recovery from inactivation, suggesting a negative modulatory role on Ca2+ entry.","method":"Yeast split-ubiquitin interaction screen, colocalization with fluorescent constructs, patch-clamp electrophysiology","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by split-ubiquitin and colocalization, functional effect by electrophysiology, single lab","pmids":["30612149"],"is_preprint":false}],"current_model":"TMEM223 is a mitochondrially localized inner membrane protein that associates with the mitochondrial ribosome, stimulates COX1 mRNA translation, and participates in early COX1/complex IV assembly intermediates; its yeast ortholog Mrx15 contacts nascent translation products via a C-terminal domain to mediate cotranslational membrane insertion and genetically interacts with the mitochondrial AAA-protease quality control system; additionally, TMEM223 has been identified as an interaction partner of neuronal CaV2.2 Ca2+ channels, where it negatively modulates channel activity."},"narrative":{"mechanistic_narrative":"TMEM223 is a mitochondrial inner-membrane protein that couples mitochondrial translation to oxidative phosphorylation complex biogenesis [PMID:34969438]. It associates with the mitochondrial ribosome and stimulates translation of COX1 mRNA, and is found within early COX1 assembly intermediates, placing it at the interface of mitoribosome activity and complex IV assembly [PMID:34969438]. Its yeast ortholog Mrx15 contacts nascent mitochondrial translation products through a soluble C-terminal domain that engages the large ribosomal subunit, acting with the ribosome receptor Mba1 in cotranslational membrane protein insertion [PMID:30091672], and genetically couples this insertion activity to i-AAA protease quality control, since loss of Mrx15 together with the protease regulators Mgr1/Mgr3 causes respiratory deficiency [PMID:30336542]. TMEM223 belongs to the TMEM70/TMEM186/TMEM223 family that co-occurs only in species possessing OXPHOS complexes, consistent with a conserved assembly role [PMID:32275929]. Separately, TMEM223 has been identified as an interaction partner of the neuronal CaV2.2 voltage-gated Ca2+ channel, where it lowers current density and alters inactivation kinetics, indicating a negative modulatory role on Ca2+ entry [PMID:30612149].","teleology":[{"year":2018,"claim":"Established the molecular basis for how this protein engages the translation machinery: the yeast ortholog Mrx15 was shown to bind the large mitoribosomal subunit via a soluble C-terminal domain and contact nascent chains during synthesis, defining a role in cotranslational membrane insertion overlapping with Mba1.","evidence":"Mass spectrometry interaction screen, ribosome co-purification, and genetic epistasis in yeast","pmids":["30091672"],"confidence":"High","gaps":["Direct demonstration in human TMEM223 not shown at this stage","Specific membrane substrates inserted via this pathway not defined","Structural detail of the ribosome contact unresolved"]},{"year":2018,"claim":"Connected membrane-insertion activity to quality control by showing Mrx15 functionally couples to the i-AAA protease, indicating that insertion and proteolytic surveillance act in a shared pathway.","evidence":"Double/triple deletion epistasis with Mgr1/Mgr3, respiratory growth and proteotoxic stress assays in yeast","pmids":["30336542"],"confidence":"Medium","gaps":["Mechanism of coupling between insertion and protease not biochemically defined","Direct protein-protein contacts with the protease not shown","Not validated in human cells"]},{"year":2019,"claim":"Identified an unexpected non-mitochondrial activity: TMEM223 binds the CaV2.2 Ca2+ channel and negatively modulates its gating, raising the possibility of a role in neuronal Ca2+ signaling.","evidence":"Yeast split-ubiquitin screen, colocalization, and patch-clamp electrophysiology","pmids":["30612149"],"confidence":"Medium","gaps":["Interaction not reconstituted with reciprocal biochemical validation in native neurons","Reconciliation with mitochondrial localization unclear","Physiological significance in vivo not established"]},{"year":2020,"claim":"Placed TMEM223 in a defined evolutionary context, showing it is a mitochondrial protein in the TMEM70/TMEM186/TMEM223 family that co-occurs only with OXPHOS complexes, supporting a conserved assembly function.","evidence":"Subcellular localization experiments plus evolutionary coevolution analysis","pmids":["32275929"],"confidence":"Medium","gaps":["Family membership inferred from coevolution, not direct functional equivalence","Specific molecular activity not assigned by this analysis"]},{"year":2021,"claim":"Directly established the human function: TMEM223 is a mitoribosome-associated protein that stimulates COX1 mRNA translation and is part of early COX1 assembly intermediates, linking mitochondrial translation to complex IV biogenesis.","evidence":"Ribosome purification, interactome analysis, and knockdown with COX1 translation and assembly-intermediate readouts in human cells","pmids":["34969438"],"confidence":"High","gaps":["Whether stimulation is direct on the ribosome or via insertion not resolved","Other OXPHOS substrates beyond COX1 not mapped","Structure of TMEM223 within assembly intermediates unknown"]},{"year":null,"claim":"How TMEM223 reconciles its mitochondrial translation/assembly role with the reported CaV2.2 channel modulation, and whether the two activities reflect distinct pools or a single mechanism, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of TMEM223","No defined catalytic activity","Dual localization/function not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0]}],"complexes":["mitochondrial ribosome (large subunit)"],"partners":["MBA1","CACNA1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A0PJW6","full_name":"Transmembrane protein 223","aliases":[],"length_aa":202,"mass_kda":22.0,"function":"Mitochondrial ribosome-associated protein involved in the first steps of cytochrome c oxidase complex (complex IV) biogenesis (PubMed:34969438). Stimulates the translation of MT-CO1 mRNA and is a constituent of early MT-CO1 assembly intermediates (PubMed:34969438)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/A0PJW6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM223","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM223","total_profiled":1310},"omim":[{"mim_id":"620435","title":"UBIQUINOL-CYTOCHROME C REDUCTASE COMPLEX ASSEMBLY FACTOR 5; UQCC5","url":"https://www.omim.org/entry/620435"},{"mim_id":"620434","title":"TRANSMEMBRANE PROTEIN 223; TMEM223","url":"https://www.omim.org/entry/620434"},{"mim_id":"620433","title":"TRANSMEMBRANE PROTEIN 186; TMEM186","url":"https://www.omim.org/entry/620433"},{"mim_id":"618812","title":"UBIQUINOL-CYTOCHROME C REDUCTASE COMPLEX ASSEMBLY FACTOR 6; UQCC6","url":"https://www.omim.org/entry/618812"},{"mim_id":"612418","title":"TRANSMEMBRANE PROTEIN 70; TMEM70","url":"https://www.omim.org/entry/612418"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM223"},"hgnc":{"alias_symbol":["MGC3196","Mrx15"],"prev_symbol":[]},"alphafold":{"accession":"A0PJW6","domains":[{"cath_id":"-","chopping":"35-69_88-195","consensus_level":"medium","plddt":84.7886,"start":35,"end":195}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0PJW6","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0PJW6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0PJW6-F1-predicted_aligned_error_v6.png","plddt_mean":73.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM223","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM223"},"sequence":{"accession":"A0PJW6","fasta_url":"https://rest.uniprot.org/uniprotkb/A0PJW6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0PJW6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0PJW6"}},"corpus_meta":[{"pmid":"32275929","id":"PMC_32275929","title":"TMEM70 functions in the assembly of complexes I and V.","date":"2020","source":"Biochimica et biophysica acta. Bioenergetics","url":"https://pubmed.ncbi.nlm.nih.gov/32275929","citation_count":38,"is_preprint":false},{"pmid":"30091672","id":"PMC_30091672","title":"The ribosome receptors Mrx15 and Mba1 jointly organize cotranslational insertion and protein biogenesis in mitochondria.","date":"2018","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/30091672","citation_count":28,"is_preprint":false},{"pmid":"34969438","id":"PMC_34969438","title":"Defining the interactome of the human mitochondrial ribosome identifies SMIM4 and TMEM223 as respiratory chain assembly factors.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34969438","citation_count":25,"is_preprint":false},{"pmid":"8826458","id":"PMC_8826458","title":"X-linked mental retardation with neonatal hypotonia in a French family (MRX15): gene assignment to Xp11.22-Xp21.1.","date":"1996","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8826458","citation_count":18,"is_preprint":false},{"pmid":"33837778","id":"PMC_33837778","title":"Vestiges of the Bacterial Signal Recognition Particle-Based Protein Targeting in Mitochondria.","date":"2021","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/33837778","citation_count":11,"is_preprint":false},{"pmid":"32783527","id":"PMC_32783527","title":"Paclitaxel Promotes Tumor-Infiltrating Macrophages in Breast Cancer.","date":"2020","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32783527","citation_count":5,"is_preprint":false},{"pmid":"33006503","id":"PMC_33006503","title":"Modulation of voltage-gated CaV2.2 Ca2+ channels by newly identified interaction partners.","date":"2020","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/33006503","citation_count":4,"is_preprint":false},{"pmid":"30612149","id":"PMC_30612149","title":"Four novel interaction partners demonstrate diverse modulatory effects on voltage-gated CaV2.2 Ca2+ channels.","date":"2019","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30612149","citation_count":4,"is_preprint":false},{"pmid":"30336542","id":"PMC_30336542","title":"Insertion Defects of Mitochondrially Encoded Proteins Burden the Mitochondrial Quality Control System.","date":"2018","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30336542","citation_count":3,"is_preprint":false},{"pmid":"41225772","id":"PMC_41225772","title":"Genetic variation in the Nr1d1 transcription factor binding site shapes metabolism-related protein networks associated with cognitive resilience in an Alzheimer's disease mouse reference panel.","date":"2025","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/41225772","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6679,"output_tokens":1405,"usd":0.020556,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8161,"output_tokens":2167,"usd":0.04749,"stage2_stop_reason":"end_turn"},"total_usd":0.068046,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM223 was identified as a ribosome-associated protein in human mitochondria that stimulates the translation of COX1 mRNA and is a constituent of early COX1 assembly intermediates, linking mitochondrial translation to complex IV biogenesis.\",\n      \"method\": \"Ribosome purification from mitochondria, interactome analysis, functional knockdown with phenotypic readout (COX1 translation and complex IV assembly intermediates)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal purification, multiple orthogonal methods (interactome, assembly intermediate profiling, translation assay), single lab but comprehensive\",\n      \"pmids\": [\"34969438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM223 (and TMEM186) are mitochondrially localized proteins in human cells, belonging to the TMEM70/TMEM186/TMEM223 protein family that co-occurs only in species with OXPHOS complexes, suggesting a conserved role in OXPHOS assembly.\",\n      \"method\": \"Subcellular localization experiments (mitochondrial localization confirmed), evolutionary coevolution analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Bioenergetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment combined with evolutionary analysis, single lab\",\n      \"pmids\": [\"32275929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast Mrx15 (ortholog of TMEM223) interacts with the large mitochondrial ribosomal subunit via a soluble C-terminal domain, contacts mitochondrial translation products during their synthesis, and plays an overlapping role with ribosome receptor Mba1 in cotranslational membrane protein insertion.\",\n      \"method\": \"Mass spectrometry-based interaction screen, ribosome co-purification, genetic epistasis (double mutant analysis)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interaction mapping plus genetic epistasis, replicated with multiple approaches in single study, consistent with human TMEM223 data\",\n      \"pmids\": [\"30091672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast Mrx15 (ortholog of TMEM223) genetically interacts with regulators of the i-AAA protease (Mgr1 and Mgr3); simultaneous absence of Mrx15 and Mgr1/Mgr3 provokes respiratory deficiency, suggesting functional coupling between mitochondrial membrane protein insertion and AAA-protease quality control.\",\n      \"method\": \"Genetic epistasis (double/triple deletion mutants), respiratory growth assay, proteotoxic stress assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in yeast, single lab, multiple mutant combinations tested\",\n      \"pmids\": [\"30336542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mrx15 (yeast ortholog of TMEM223) is broadly conserved in eukaryotes and is a mitochondrial ribosome-interacting protein implicated in membrane protein targeting, functionally nonredundant with the mitochondrial SRP system.\",\n      \"method\": \"Phylogenetic/comparative genomics with experimental confirmation of mitochondrial localization in model organisms\",\n      \"journal\": \"Molecular biology and evolution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily comparative/evolutionary analysis; direct functional experiments are in other organisms and not specifically on TMEM223\",\n      \"pmids\": [\"33837778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMEM223 interacts with the CaV2.2 voltage-gated Ca2+ channel (domain IV), lowers average current density, accelerates cumulative current inactivation kinetics, and slows recovery from inactivation, suggesting a negative modulatory role on Ca2+ entry.\",\n      \"method\": \"Yeast split-ubiquitin interaction screen, colocalization with fluorescent constructs, patch-clamp electrophysiology\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by split-ubiquitin and colocalization, functional effect by electrophysiology, single lab\",\n      \"pmids\": [\"30612149\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM223 is a mitochondrially localized inner membrane protein that associates with the mitochondrial ribosome, stimulates COX1 mRNA translation, and participates in early COX1/complex IV assembly intermediates; its yeast ortholog Mrx15 contacts nascent translation products via a C-terminal domain to mediate cotranslational membrane insertion and genetically interacts with the mitochondrial AAA-protease quality control system; additionally, TMEM223 has been identified as an interaction partner of neuronal CaV2.2 Ca2+ channels, where it negatively modulates channel activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM223 is a mitochondrial inner-membrane protein that couples mitochondrial translation to oxidative phosphorylation complex biogenesis [#0]. It associates with the mitochondrial ribosome and stimulates translation of COX1 mRNA, and is found within early COX1 assembly intermediates, placing it at the interface of mitoribosome activity and complex IV assembly [#0]. Its yeast ortholog Mrx15 contacts nascent mitochondrial translation products through a soluble C-terminal domain that engages the large ribosomal subunit, acting with the ribosome receptor Mba1 in cotranslational membrane protein insertion [#2], and genetically couples this insertion activity to i-AAA protease quality control, since loss of Mrx15 together with the protease regulators Mgr1/Mgr3 causes respiratory deficiency [#3]. TMEM223 belongs to the TMEM70/TMEM186/TMEM223 family that co-occurs only in species possessing OXPHOS complexes, consistent with a conserved assembly role [#1]. Separately, TMEM223 has been identified as an interaction partner of the neuronal CaV2.2 voltage-gated Ca2+ channel, where it lowers current density and alters inactivation kinetics, indicating a negative modulatory role on Ca2+ entry [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the molecular basis for how this protein engages the translation machinery: the yeast ortholog Mrx15 was shown to bind the large mitoribosomal subunit via a soluble C-terminal domain and contact nascent chains during synthesis, defining a role in cotranslational membrane insertion overlapping with Mba1.\",\n      \"evidence\": \"Mass spectrometry interaction screen, ribosome co-purification, and genetic epistasis in yeast\",\n      \"pmids\": [\"30091672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration in human TMEM223 not shown at this stage\", \"Specific membrane substrates inserted via this pathway not defined\", \"Structural detail of the ribosome contact unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected membrane-insertion activity to quality control by showing Mrx15 functionally couples to the i-AAA protease, indicating that insertion and proteolytic surveillance act in a shared pathway.\",\n      \"evidence\": \"Double/triple deletion epistasis with Mgr1/Mgr3, respiratory growth and proteotoxic stress assays in yeast\",\n      \"pmids\": [\"30336542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of coupling between insertion and protease not biochemically defined\", \"Direct protein-protein contacts with the protease not shown\", \"Not validated in human cells\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an unexpected non-mitochondrial activity: TMEM223 binds the CaV2.2 Ca2+ channel and negatively modulates its gating, raising the possibility of a role in neuronal Ca2+ signaling.\",\n      \"evidence\": \"Yeast split-ubiquitin screen, colocalization, and patch-clamp electrophysiology\",\n      \"pmids\": [\"30612149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not reconstituted with reciprocal biochemical validation in native neurons\", \"Reconciliation with mitochondrial localization unclear\", \"Physiological significance in vivo not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed TMEM223 in a defined evolutionary context, showing it is a mitochondrial protein in the TMEM70/TMEM186/TMEM223 family that co-occurs only with OXPHOS complexes, supporting a conserved assembly function.\",\n      \"evidence\": \"Subcellular localization experiments plus evolutionary coevolution analysis\",\n      \"pmids\": [\"32275929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Family membership inferred from coevolution, not direct functional equivalence\", \"Specific molecular activity not assigned by this analysis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Directly established the human function: TMEM223 is a mitoribosome-associated protein that stimulates COX1 mRNA translation and is part of early COX1 assembly intermediates, linking mitochondrial translation to complex IV biogenesis.\",\n      \"evidence\": \"Ribosome purification, interactome analysis, and knockdown with COX1 translation and assembly-intermediate readouts in human cells\",\n      \"pmids\": [\"34969438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stimulation is direct on the ribosome or via insertion not resolved\", \"Other OXPHOS substrates beyond COX1 not mapped\", \"Structure of TMEM223 within assembly intermediates unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM223 reconciles its mitochondrial translation/assembly role with the reported CaV2.2 channel modulation, and whether the two activities reflect distinct pools or a single mechanism, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of TMEM223\", \"No defined catalytic activity\", \"Dual localization/function not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"mitochondrial ribosome (large subunit)\"],\n    \"partners\": [\"MBA1\", \"CACNA1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}