{"gene":"TMEM177","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2017,"finding":"TMEM177 is a constituent of the COX20 interaction network in the inner mitochondrial membrane; loss or overexpression of TMEM177 affects COX20 abundance, and TMEM177 associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner, promoting COX2 assembly at the level of CuA-site formation.","method":"Co-immunoprecipitation, loss-of-function and gain-of-function experiments in human cells, interaction network analysis","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP/interaction network analysis combined with both loss- and gain-of-function experiments establishing the COX20-dependent mechanism and functional consequence on COX2 assembly","pmids":["29154948"],"is_preprint":false},{"year":2025,"finding":"In vivo knockout of Tmem177 in mice moderately reduces COX20 levels but preserves OXPHOS complexes; TMEM177 was also identified as an interactor of mitochondrial ribosomes; Tmem177/Surf1 double-knockout mice are born asymptomatic, indicating TMEM177 fine-tunes complex IV assembly by stabilizing COX20 rather than being essential for it.","method":"Tmem177 knockout mice, Tmem177/Surf1 double-knockout mice, analysis of mitochondrial gene expression and OXPHOS complex activity/assembly, mitochondrial ribosome interaction studies","journal":"Mitochondrion","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean in vivo knockout with defined phenotypic and biochemical readouts, double-knockout epistasis, single lab but multiple orthogonal methods","pmids":["41253195"],"is_preprint":false},{"year":2026,"finding":"Knockdown of TMEM177 in CRC cells disrupts mitochondrial membrane potential and reduces OXPHOS pathway activity, producing anti-cancer effects; E2/ERα-mediated promoter hypermethylation reduces TMEM177 expression, and this epigenetic silencing is reversed by the demethylating agent 5-Aza-2-deoxycytidine.","method":"siRNA knockdown in HCT-116 and SW480 CRC cell lines, mitochondrial membrane potential assay, OXPHOS activity measurement, 5-Aza-2-deoxycytidine treatment, ERα silencing","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — knockdown with defined mitochondrial phenotype readouts and epigenetic mechanism, single lab, functional role consistent with known COX2 assembly role","pmids":["41597199"],"is_preprint":false}],"current_model":"TMEM177 is a mitochondrial inner membrane protein that stabilizes the chaperone COX20 and associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner, promoting copper (CuA-site) delivery to COX2 during cytochrome c oxidase (complex IV) assembly; in vivo, it fine-tunes complex IV assembly and interacts with mitochondrial ribosomes, but is not essential for OXPHOS complex integrity."},"narrative":{"mechanistic_narrative":"TMEM177 is a mitochondrial inner membrane protein that participates in cytochrome c oxidase (complex IV) biogenesis by acting within the COX20 chaperone network [PMID:29154948]. It physically associates with COX20 and, in a COX20-dependent manner, with newly synthesized COX2 and the metallochaperone SCO2, promoting CuA-site formation on COX2 during complex IV assembly; loss or overexpression of TMEM177 reciprocally alters COX20 abundance, identifying it as a stabilizer of COX20 [PMID:29154948]. In vivo, TMEM177 fine-tunes rather than gates this process: knockout mice show moderately reduced COX20 but intact OXPHOS complexes, and Tmem177/Surf1 double-knockout mice are born asymptomatic, indicating TMEM177 is not essential for complex IV integrity; TMEM177 also associates with mitochondrial ribosomes [PMID:41253195]. Functionally, depletion of TMEM177 disrupts mitochondrial membrane potential and lowers OXPHOS activity, and its expression is silenced by E2/ERα-driven promoter hypermethylation that is reversible with a demethylating agent [PMID:41597199].","teleology":[{"year":2017,"claim":"Established TMEM177's molecular role by placing it within the COX20 chaperone network and linking it mechanistically to CuA-site formation on COX2, answering how it contributes to complex IV assembly.","evidence":"Co-IP, interaction network analysis, and loss/gain-of-function in human cells","pmids":["29154948"],"confidence":"High","gaps":["Structural basis of the TMEM177-COX20 interaction not resolved","Whether TMEM177 acts catalytically or purely as a scaffold for copper delivery is undefined","Direct copper-handling activity not demonstrated"]},{"year":2025,"claim":"Resolved whether TMEM177 is essential for OXPHOS by showing in vivo it only fine-tunes complex IV assembly via COX20 stabilization, and broadened its interactome to mitochondrial ribosomes.","evidence":"Tmem177 single- and Tmem177/Surf1 double-knockout mice with OXPHOS assembly/activity readouts and ribosome interaction studies","pmids":["41253195"],"confidence":"High","gaps":["Functional significance of the mitochondrial ribosome association not defined","Compensatory mechanisms preserving OXPHOS in the knockout not identified","Tissue-specific roles not dissected"]},{"year":2026,"claim":"Connected TMEM177 expression control to estrogen signaling and showed its depletion impairs mitochondrial bioenergetics in colorectal cancer cells, framing it as an epigenetically regulated metabolic node.","evidence":"siRNA knockdown in CRC cell lines, membrane potential/OXPHOS assays, ERα silencing, and 5-Aza-2-deoxycytidine treatment","pmids":["41597199"],"confidence":"Medium","gaps":["Single-lab study with knockdown rather than genetic loss","Direct binding of ERα to the TMEM177 promoter not shown in this synthesis","In vivo relevance of the cancer phenotype not established"]},{"year":null,"claim":"How TMEM177 mechanistically couples COX20 stabilization, copper delivery, and mitochondrial ribosome association into a single biogenesis step remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of TMEM177 or its complexes","Functional role of ribosome association unknown","Whether TMEM177 directly handles copper versus scaffolding SCO2 is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["COX20","COX2","SCO2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53S58","full_name":"Transmembrane protein 177","aliases":[],"length_aa":311,"mass_kda":33.8,"function":"Plays a role in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation and is required for the stabilization of COX20 and the newly synthesized MT-CO2/COX2 protein","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q53S58/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM177","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/TMEM177","total_profiled":1310},"omim":[{"mim_id":"620752","title":"TRANSMEMBRANE PROTEIN 177; TMEM177","url":"https://www.omim.org/entry/620752"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM177"},"hgnc":{"alias_symbol":["MGC10993"],"prev_symbol":[]},"alphafold":{"accession":"Q53S58","domains":[{"cath_id":"-","chopping":"36-169_225-307","consensus_level":"medium","plddt":91.6948,"start":36,"end":307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53S58","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53S58-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53S58-F1-predicted_aligned_error_v6.png","plddt_mean":90.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM177","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM177"},"sequence":{"accession":"Q53S58","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53S58.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53S58/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53S58"}},"corpus_meta":[{"pmid":"29154948","id":"PMC_29154948","title":"The mitochondrial TMEM177 associates with COX20 during COX2 biogenesis.","date":"2017","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29154948","citation_count":29,"is_preprint":false},{"pmid":"41597199","id":"PMC_41597199","title":"Estrogen-Induced Hypermethylation Silencing of RPS2 and TMEM177 Inhibits Energy Metabolism and Reduces the Survival of CRC Cells.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41597199","citation_count":0,"is_preprint":false},{"pmid":"41253195","id":"PMC_41253195","title":"The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.","date":"2025","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/41253195","citation_count":0,"is_preprint":false},{"pmid":"41106624","id":"PMC_41106624","title":"Multi-omics causal inference of nuclear-encoded mitochondrial genes in autism spectrum disorder.","date":"2025","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/41106624","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4151,"output_tokens":913,"usd":0.013074,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7419,"output_tokens":1589,"usd":0.03841,"stage2_stop_reason":"end_turn"},"total_usd":0.051484,"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\": 2017,\n      \"finding\": \"TMEM177 is a constituent of the COX20 interaction network in the inner mitochondrial membrane; loss or overexpression of TMEM177 affects COX20 abundance, and TMEM177 associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner, promoting COX2 assembly at the level of CuA-site formation.\",\n      \"method\": \"Co-immunoprecipitation, loss-of-function and gain-of-function experiments in human cells, interaction network analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP/interaction network analysis combined with both loss- and gain-of-function experiments establishing the COX20-dependent mechanism and functional consequence on COX2 assembly\",\n      \"pmids\": [\"29154948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vivo knockout of Tmem177 in mice moderately reduces COX20 levels but preserves OXPHOS complexes; TMEM177 was also identified as an interactor of mitochondrial ribosomes; Tmem177/Surf1 double-knockout mice are born asymptomatic, indicating TMEM177 fine-tunes complex IV assembly by stabilizing COX20 rather than being essential for it.\",\n      \"method\": \"Tmem177 knockout mice, Tmem177/Surf1 double-knockout mice, analysis of mitochondrial gene expression and OXPHOS complex activity/assembly, mitochondrial ribosome interaction studies\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo knockout with defined phenotypic and biochemical readouts, double-knockout epistasis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41253195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of TMEM177 in CRC cells disrupts mitochondrial membrane potential and reduces OXPHOS pathway activity, producing anti-cancer effects; E2/ERα-mediated promoter hypermethylation reduces TMEM177 expression, and this epigenetic silencing is reversed by the demethylating agent 5-Aza-2-deoxycytidine.\",\n      \"method\": \"siRNA knockdown in HCT-116 and SW480 CRC cell lines, mitochondrial membrane potential assay, OXPHOS activity measurement, 5-Aza-2-deoxycytidine treatment, ERα silencing\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — knockdown with defined mitochondrial phenotype readouts and epigenetic mechanism, single lab, functional role consistent with known COX2 assembly role\",\n      \"pmids\": [\"41597199\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM177 is a mitochondrial inner membrane protein that stabilizes the chaperone COX20 and associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner, promoting copper (CuA-site) delivery to COX2 during cytochrome c oxidase (complex IV) assembly; in vivo, it fine-tunes complex IV assembly and interacts with mitochondrial ribosomes, but is not essential for OXPHOS complex integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM177 is a mitochondrial inner membrane protein that participates in cytochrome c oxidase (complex IV) biogenesis by acting within the COX20 chaperone network [#0]. It physically associates with COX20 and, in a COX20-dependent manner, with newly synthesized COX2 and the metallochaperone SCO2, promoting CuA-site formation on COX2 during complex IV assembly; loss or overexpression of TMEM177 reciprocally alters COX20 abundance, identifying it as a stabilizer of COX20 [#0]. In vivo, TMEM177 fine-tunes rather than gates this process: knockout mice show moderately reduced COX20 but intact OXPHOS complexes, and Tmem177/Surf1 double-knockout mice are born asymptomatic, indicating TMEM177 is not essential for complex IV integrity; TMEM177 also associates with mitochondrial ribosomes [#1]. Functionally, depletion of TMEM177 disrupts mitochondrial membrane potential and lowers OXPHOS activity, and its expression is silenced by E2/ERα-driven promoter hypermethylation that is reversible with a demethylating agent [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established TMEM177's molecular role by placing it within the COX20 chaperone network and linking it mechanistically to CuA-site formation on COX2, answering how it contributes to complex IV assembly.\",\n      \"evidence\": \"Co-IP, interaction network analysis, and loss/gain-of-function in human cells\",\n      \"pmids\": [\"29154948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the TMEM177-COX20 interaction not resolved\", \"Whether TMEM177 acts catalytically or purely as a scaffold for copper delivery is undefined\", \"Direct copper-handling activity not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved whether TMEM177 is essential for OXPHOS by showing in vivo it only fine-tunes complex IV assembly via COX20 stabilization, and broadened its interactome to mitochondrial ribosomes.\",\n      \"evidence\": \"Tmem177 single- and Tmem177/Surf1 double-knockout mice with OXPHOS assembly/activity readouts and ribosome interaction studies\",\n      \"pmids\": [\"41253195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of the mitochondrial ribosome association not defined\", \"Compensatory mechanisms preserving OXPHOS in the knockout not identified\", \"Tissue-specific roles not dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected TMEM177 expression control to estrogen signaling and showed its depletion impairs mitochondrial bioenergetics in colorectal cancer cells, framing it as an epigenetically regulated metabolic node.\",\n      \"evidence\": \"siRNA knockdown in CRC cell lines, membrane potential/OXPHOS assays, ERα silencing, and 5-Aza-2-deoxycytidine treatment\",\n      \"pmids\": [\"41597199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study with knockdown rather than genetic loss\", \"Direct binding of ERα to the TMEM177 promoter not shown in this synthesis\", \"In vivo relevance of the cancer phenotype not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM177 mechanistically couples COX20 stabilization, copper delivery, and mitochondrial ribosome association into a single biogenesis step remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of TMEM177 or its complexes\", \"Functional role of ribosome association unknown\", \"Whether TMEM177 directly handles copper versus scaffolding SCO2 is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"COX20\", \"COX2\", \"SCO2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}