{"gene":"TMEM186","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2020,"finding":"TMEM186 is a bona fide component of the mitochondrial complex I intermediate assembly (MCIA) complex (alongside NDUFAF1, ECSIT, ACAD9, and TMEM126B); loss of TMEM186 causes MCIA complex defects and reduced complex I assembly, and TMEM186 enriches with newly translated ND3, indicating a role in building the ND2-module.","method":"Cell knockout studies, co-immunoprecipitation, complexome profiling, metabolic labeling to track newly translated mitochondrial subunits","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction validated by multiple orthogonal methods (KO phenotype, complexome profiling, co-enrichment with nascent ND3) in a single rigorous study","pmids":["32320651"],"is_preprint":false},{"year":2020,"finding":"TMEM186 is a mitochondrial inner membrane protein belonging to the TMEM70/TMEM186/TMEM223 protein family; TMEM186 (and TMEM223) are confirmed to be mitochondrially localized in human cells, and the family is restricted to species that possess OXPHOS complexes, consistent with a conserved role in OXPHOS assembly.","method":"BioID proximity labeling, complexome profiling, evolutionary coevolution analyses, subcellular localization experiments","journal":"Biochimica et Biophysica Acta. Bioenergetics","confidence":"Medium","confidence_rationale":"Tier 2 — mitochondrial localization confirmed experimentally and supported by evolutionary analysis, but functional mechanistic detail for TMEM186 specifically is secondary to the TMEM70 focus of the study","pmids":["32275929"],"is_preprint":false}],"current_model":"TMEM186 is a mitochondrial inner membrane protein and bona fide subunit of the MCIA assembly complex that co-enriches with newly translated ND3 and is required for biogenesis of the ND2-module of mitochondrial respiratory chain complex I."},"narrative":{"teleology":[{"year":2020,"claim":"Establishing that TMEM186 is a mitochondrial inner membrane protein belonging to an OXPHOS-associated family resolved its subcellular localization and placed it in an evolutionary context consistent with a role in respiratory chain biogenesis.","evidence":"BioID proximity labeling, subcellular localization experiments, and evolutionary coevolution analyses in human cells","pmids":["32275929"],"confidence":"Medium","gaps":["Study was primarily focused on TMEM70; functional role of TMEM186 itself was not directly dissected","No structural data for TMEM186 or its topology within the inner membrane"]},{"year":2020,"claim":"Identifying TMEM186 as a bona fide MCIA complex subunit whose knockout disrupts complex I assembly and whose association with nascent ND3 defines its specific role in ND2-module biogenesis answered the key question of what TMEM186 does mechanistically in mitochondria.","evidence":"Cell knockout studies, co-immunoprecipitation, complexome profiling, and metabolic labeling of newly translated mitochondrial subunits in human cells","pmids":["32320651"],"confidence":"High","gaps":["Precise molecular mechanism by which TMEM186 facilitates ND3 incorporation into the ND2-module is unknown","Whether TMEM186 loss causes human disease has not been reported","No reconstitution of TMEM186 function with purified MCIA components"]},{"year":null,"claim":"It remains unknown how TMEM186 biochemically contributes to ND3/ND2-module assembly within the MCIA complex, whether it has enzymatic or purely structural roles, and whether TMEM186 mutations cause mitochondrial disease in humans.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of TMEM186 within the MCIA complex","No patient mutations or disease association reported","Catalytic versus scaffolding role undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1]}],"complexes":["MCIA complex"],"partners":["NDUFAF1","ECSIT","ACAD9","TMEM126B"],"other_free_text":[]},"mechanistic_narrative":"TMEM186 is a mitochondrial inner membrane protein and bona fide subunit of the MCIA (mitochondrial complex I intermediate assembly) complex, which includes NDUFAF1, ECSIT, ACAD9, and TMEM126B; loss of TMEM186 disrupts MCIA complex integrity and impairs complex I assembly [PMID:32320651]. TMEM186 enriches with newly translated ND3, establishing a direct role in biogenesis of the ND2-module of respiratory chain complex I [PMID:32320651]. TMEM186 belongs to the TMEM70/TMEM186/TMEM223 protein family, which is restricted to species possessing OXPHOS complexes, consistent with a conserved function in oxidative phosphorylation assembly [PMID:32275929]."},"prefetch_data":{"uniprot":{"accession":"Q96B77","full_name":"Transmembrane protein 186","aliases":[],"length_aa":213,"mass_kda":24.9,"function":"As part of the MCIA complex, required for efficient assembly of the mitochondrial complex I","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q96B77/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM186","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM186","total_profiled":1310},"omim":[{"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":"612418","title":"TRANSMEMBRANE PROTEIN 70; TMEM70","url":"https://www.omim.org/entry/612418"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM186"},"hgnc":{"alias_symbol":["DKFZP564K2062"],"prev_symbol":["C16orf51"]},"alphafold":{"accession":"Q96B77","domains":[{"cath_id":"-","chopping":"61-208","consensus_level":"medium","plddt":70.7151,"start":61,"end":208}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96B77","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96B77-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96B77-F1-predicted_aligned_error_v6.png","plddt_mean":60.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM186","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM186"},"sequence":{"accession":"Q96B77","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96B77.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96B77/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96B77"}},"corpus_meta":[{"pmid":"32320651","id":"PMC_32320651","title":"Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly Complex Factors in the Biogenesis of Complex I.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32320651","citation_count":82,"is_preprint":false},{"pmid":"32275929","id":"PMC_32275929","title":"TMEM70 functions in the assembly of complexes I and V.","date":"2020","source":"Biochimica et biophysica acta. 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Bioenergetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mitochondrial localization confirmed experimentally and supported by evolutionary analysis, but functional mechanistic detail for TMEM186 specifically is secondary to the TMEM70 focus of the study\",\n      \"pmids\": [\"32275929\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM186 is a mitochondrial inner membrane protein and bona fide subunit of the MCIA assembly complex that co-enriches with newly translated ND3 and is required for biogenesis of the ND2-module of mitochondrial respiratory chain complex I.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMEM186 is a mitochondrial inner membrane protein and bona fide subunit of the MCIA (mitochondrial complex I intermediate assembly) complex, which includes NDUFAF1, ECSIT, ACAD9, and TMEM126B; loss of TMEM186 disrupts MCIA complex integrity and impairs complex I assembly [PMID:32320651]. TMEM186 enriches with newly translated ND3, establishing a direct role in biogenesis of the ND2-module of respiratory chain complex I [PMID:32320651]. TMEM186 belongs to the TMEM70/TMEM186/TMEM223 protein family, which is restricted to species possessing OXPHOS complexes, consistent with a conserved function in oxidative phosphorylation assembly [PMID:32275929].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that TMEM186 is a mitochondrial inner membrane protein belonging to an OXPHOS-associated family resolved its subcellular localization and placed it in an evolutionary context consistent with a role in respiratory chain biogenesis.\",\n      \"evidence\": \"BioID proximity labeling, subcellular localization experiments, and evolutionary coevolution analyses in human cells\",\n      \"pmids\": [\"32275929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Study was primarily focused on TMEM70; functional role of TMEM186 itself was not directly dissected\",\n        \"No structural data for TMEM186 or its topology within the inner membrane\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying TMEM186 as a bona fide MCIA complex subunit whose knockout disrupts complex I assembly and whose association with nascent ND3 defines its specific role in ND2-module biogenesis answered the key question of what TMEM186 does mechanistically in mitochondria.\",\n      \"evidence\": \"Cell knockout studies, co-immunoprecipitation, complexome profiling, and metabolic labeling of newly translated mitochondrial subunits in human cells\",\n      \"pmids\": [\"32320651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise molecular mechanism by which TMEM186 facilitates ND3 incorporation into the ND2-module is unknown\",\n        \"Whether TMEM186 loss causes human disease has not been reported\",\n        \"No reconstitution of TMEM186 function with purified MCIA components\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how TMEM186 biochemically contributes to ND3/ND2-module assembly within the MCIA complex, whether it has enzymatic or purely structural roles, and whether TMEM186 mutations cause mitochondrial disease in humans.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of TMEM186 within the MCIA complex\",\n        \"No patient mutations or disease association reported\",\n        \"Catalytic versus scaffolding role undetermined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005739\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1852241\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"complexes\": [\n      \"MCIA complex\"\n    ],\n    \"partners\": [\n      \"NDUFAF1\",\n      \"ECSIT\",\n      \"ACAD9\",\n      \"TMEM126B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}