{"gene":"CMC1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2017,"finding":"CMC1 forms an early cytochrome c oxidase (CIV) assembly intermediate with COX1 and two assembly factors COA3 and COX14 in the mitochondrial intermembrane space. CMC1 stabilizes the COX1-COA3-COX14 complex prior to incorporation of COX4 and COX5a subunits. CMC1 knockout results in normal COX1 synthesis but decreased CIV activity due to instability of newly synthesized COX1, demonstrating that CMC1 regulates COX1 turnover without affecting translation rate.","method":"TALEN-mediated CMC1 knockout HEK293T cell line, co-immunoprecipitation of assembly intermediates, metabolic labeling of mitochondrial translation products, CIV activity assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP of assembly complex, KO cell line with defined phenotype, multiple orthogonal methods (translation labeling, activity assay, epistasis with COX10/COX11/SURF1/MITRAC7)","pmids":["28082314"],"is_preprint":false},{"year":2010,"finding":"Yeast Cmc1 (ortholog of human CMC1) is a mitochondrial intermembrane space twin CX9C protein required for cytochrome c oxidase biogenesis. Cmc1 physically interacts with Cmc2, and absence of Cmc2 causes a 5-fold increase in Cmc1 accumulation in mitochondrial membranes. CMC1 overexpression does not rescue the respiratory defect of cmc2 mutants, indicating cooperative but non-overlapping functions.","method":"Co-immunoprecipitation (physical interaction between Cmc1 and Cmc2), spectrophotometric CIV activity assay, polarographic respiration measurement, genetic complementation/overexpression experiments in yeast","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, enzymatic activity assays, genetic epistasis, conservation validated in C. elegans knockdown","pmids":["20220131"],"is_preprint":false},{"year":2012,"finding":"CMC1 (yeast ortholog) is imported into the mitochondrial intermembrane space via the Mia40-Erv1 oxidative folding pathway. CMC1 forms a stable intermediate with Mia40 and is released in the presence of Erv1. All three proteins (Cmc1, Mia40, Erv1) form a ternary complex in mitochondria. Efficient oxidative folding of Cmc1 requires both Erv1 and Mia40 together, preventing non-native disulfide bond formation.","method":"In vitro oxidative folding assay, in organello import assay, co-immunoprecipitation of ternary complex (Cmc1-Mia40-Erv1)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of import/folding pathway combined with in organello co-IP, multiple orthogonal methods in one study","pmids":["22767599"],"is_preprint":false},{"year":2024,"finding":"CMC1 acts as a positive regulator of CD8+ T cell activation and terminal differentiation. Loss of Cmc1 inhibits CD8+ T cell exhaustion and promotes differentiation into metabolically quiescent memory-like cells with increased tolerance to cell death. Environmental lactate enhances CMC1 expression by inducing USP7-mediated stabilization and de-ubiquitination of CMC1 protein, linking the lactate-enriched tumor microenvironment to CD8+ T cell dysfunction via CMC1.","method":"Cmc1 knockout mice, in vitro T cell culture system, B16-OVA tumor model, mechanistic study of USP7-mediated de-ubiquitination of CMC1","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype in vivo and in vitro, USP7-CMC1 interaction described but full biochemical reconstitution not explicitly stated in abstract","pmids":["38659649"],"is_preprint":false}],"current_model":"Human CMC1 is a mitochondrial intermembrane space twin CX9C protein that is imported via the Mia40-Erv1 oxidative folding pathway, where it forms an early cytochrome c oxidase assembly intermediate with COX1, COA3, and COX14 to stabilize newly synthesized COX1 prior to subunit incorporation and metallation; additionally, CMC1 expression in CD8+ T cells is stabilized by USP7-mediated de-ubiquitination in response to lactate, where it promotes T cell activation and exhaustion."},"narrative":{"mechanistic_narrative":"CMC1 is a mitochondrial intermembrane space twin CX9C protein that functions in the biogenesis of cytochrome c oxidase (complex IV) [PMID:28082314, PMID:20220131]. It is imported into the intermembrane space and oxidatively folded through the Mia40-Erv1 disulfide relay, forming a stable Cmc1-Mia40 intermediate that is resolved by Erv1, with both factors together required to prevent non-native disulfide bond formation [PMID:22767599]. Within complex IV assembly, CMC1 forms an early intermediate with newly synthesized COX1 and the assembly factors COA3 and COX14, stabilizing the COX1-COA3-COX14 module prior to incorporation of COX4 and COX5a; loss of CMC1 does not affect COX1 translation rate but accelerates COX1 turnover and lowers complex IV activity, establishing CMC1 as a stabilizer of nascent COX1 [PMID:28082314]. In yeast it cooperates with the partner protein Cmc2 in a non-redundant manner [PMID:20220131]. Beyond its mitochondrial role, CMC1 acts as a positive regulator of CD8+ T cell activation and terminal differentiation, where USP7-mediated de-ubiquitination stabilizes CMC1 in response to environmental lactate, linking the lactate-rich tumor microenvironment to CD8+ T cell exhaustion [PMID:38659649].","teleology":[{"year":2010,"claim":"Established that CMC1 is an intermembrane space twin CX9C protein required for cytochrome c oxidase biogenesis and that it acts in cooperation with a partner protein, defining its compartment and functional category.","evidence":"Co-immunoprecipitation, spectrophotometric CIV activity and respiration assays, and genetic complementation in yeast, with conservation validated in C. elegans knockdown","pmids":["20220131"],"confidence":"High","gaps":["Molecular substrate/client of Cmc1 within CIV assembly not yet defined","Mechanism of cooperation with Cmc2 unresolved","Human ortholog not yet characterized"]},{"year":2012,"claim":"Resolved how CMC1 reaches and folds in the intermembrane space, showing it is a Mia40-Erv1 oxidative folding substrate that transits a ternary import intermediate.","evidence":"In vitro oxidative folding assay, in organello import, and co-IP of the Cmc1-Mia40-Erv1 ternary complex in yeast","pmids":["22767599"],"confidence":"High","gaps":["Which cysteines form the functional disulfides not mapped","Does folding state gate CIV assembly function unclear","Human import not directly tested"]},{"year":2017,"claim":"Defined the precise role of human CMC1 in complex IV assembly, showing it stabilizes the early COX1-COA3-COX14 intermediate and protects nascent COX1 from degradation rather than affecting its synthesis.","evidence":"TALEN CMC1 knockout HEK293T cells, co-IP of assembly intermediates, metabolic labeling of mitochondrial translation, and CIV activity assays","pmids":["28082314"],"confidence":"High","gaps":["Structural basis of COX1 stabilization not determined","How CMC1 is released as assembly proceeds unknown","Link to COX1 metallation not mechanistically dissected"]},{"year":2024,"claim":"Extended CMC1 beyond mitochondrial assembly to immune regulation, showing its lactate- and USP7-controlled stability drives CD8+ T cell activation and exhaustion.","evidence":"Cmc1 knockout mice, in vitro T cell culture, B16-OVA tumor model, and study of USP7-mediated de-ubiquitination","pmids":["38659649"],"confidence":"Medium","gaps":["Full biochemical reconstitution of the USP7-CMC1 interaction not established","Whether the immune phenotype derives from CMC1's CIV assembly role or a distinct function unclear","Ubiquitination sites on CMC1 not mapped"]},{"year":null,"claim":"How CMC1's mitochondrial complex IV assembly activity mechanistically connects to its regulation of CD8+ T cell differentiation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CMC1 in the COX1 assembly intermediate","Metabolic link between CIV function and T cell fate not defined","Whether USP7 acts on the mitochondrial pool of CMC1 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0]}],"complexes":["COX1-COA3-COX14 complex IV assembly intermediate"],"partners":["COX1","COA3","COX14","CMC2","MIA40","ERV1","USP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z7K0","full_name":"COX assembly mitochondrial protein homolog","aliases":[],"length_aa":106,"mass_kda":12.5,"function":"Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q7Z7K0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CMC1","classification":"Not Classified","n_dependent_lines":96,"n_total_lines":1208,"dependency_fraction":0.07947019867549669},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CMC1","total_profiled":1310},"omim":[{"mim_id":"615166","title":"C-X9-C MOTIF-CONTAINING 1; CMC1","url":"https://www.omim.org/entry/615166"},{"mim_id":"608354","title":"CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 1; CMAVM1","url":"https://www.omim.org/entry/608354"},{"mim_id":"607850","title":"OSTEOARTHRITIS SUSCEPTIBILITY 3; OS3","url":"https://www.omim.org/entry/607850"},{"mim_id":"602089","title":"HEMANGIOMA, CAPILLARY INFANTILE","url":"https://www.omim.org/entry/602089"},{"mim_id":"600998","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, Q POLYPEPTIDE; GNAQ","url":"https://www.omim.org/entry/600998"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CMC1"},"hgnc":{"alias_symbol":["MGC61571"],"prev_symbol":["C3orf68"]},"alphafold":{"accession":"Q7Z7K0","domains":[{"cath_id":"-","chopping":"24-90","consensus_level":"high","plddt":93.5391,"start":24,"end":90}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7K0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7K0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7K0-F1-predicted_aligned_error_v6.png","plddt_mean":87.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CMC1","jax_strain_url":"https://www.jax.org/strain/search?query=CMC1"},"sequence":{"accession":"Q7Z7K0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z7K0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z7K0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7K0"}},"corpus_meta":[{"pmid":"28082314","id":"PMC_28082314","title":"A CMC1-knockout reveals translation-independent control of human mitochondrial complex IV biogenesis.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/28082314","citation_count":64,"is_preprint":false},{"pmid":"18704277","id":"PMC_18704277","title":"Catalytic and thermodynamic characterization of endoglucanase (CMCase) from Aspergillus oryzae cmc-1.","date":"2008","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/18704277","citation_count":47,"is_preprint":false},{"pmid":"19010064","id":"PMC_19010064","title":"High hand joint mobility is associated with radiological CMC1 osteoarthritis: the AGES-Reykjavik study.","date":"2008","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/19010064","citation_count":41,"is_preprint":false},{"pmid":"20220131","id":"PMC_20220131","title":"The conserved mitochondrial twin Cx9C protein Cmc2 Is a Cmc1 homologue essential for cytochrome c oxidase biogenesis.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20220131","citation_count":34,"is_preprint":false},{"pmid":"22767599","id":"PMC_22767599","title":"Role of twin Cys-Xaa9-Cys motif cysteines in mitochondrial import of the cytochrome C oxidase biogenesis factor Cmc1.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22767599","citation_count":24,"is_preprint":false},{"pmid":"38659649","id":"PMC_38659649","title":"The potential role of CMC1 as an immunometabolic checkpoint in T cell immunity.","date":"2024","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/38659649","citation_count":12,"is_preprint":false},{"pmid":"18661108","id":"PMC_18661108","title":"Improvement of Aspergillus oryzae for hyperproduction of endoglucanase: expression cloning of cmc-1 gene of Aspergillus aculeatus.","date":"2008","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/18661108","citation_count":9,"is_preprint":false},{"pmid":"39513308","id":"PMC_39513308","title":"The Risk Genes S1PR5, CMC1, and ASAH1 as Potential Targets for the Diagnosis, Immunotherapy, and Treatment of Colon Adenocarcinoma by Single-Cell and Bulk RNA Sequencing Analysis.","date":"2024","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39513308","citation_count":8,"is_preprint":false},{"pmid":"32060600","id":"PMC_32060600","title":"Directed modification of a ruminal cellulase gene (CMC-1) from a metagenomic library isolated from Yunnan gayal (Bos frontalis).","date":"2020","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32060600","citation_count":6,"is_preprint":false},{"pmid":"9933935","id":"PMC_9933935","title":"Cloning and complete nucleotide sequence of Acinetobacter radioresistens CMC-1 AglyA gene encoding serine hydroxymethyltransferase.","date":"1999","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/9933935","citation_count":3,"is_preprint":false},{"pmid":"41688906","id":"PMC_41688906","title":"Transcriptomics and proteomics insights into carotenoid differentiation in tissue cultured Rehmannia glutinosa root cambial meristematic cells: REG-CMC1 and non-somaclonal REG-CMC2.","date":"2026","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/41688906","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.16.682832","title":"Decoding the human PBMC isonome: Isoform-level resolution with single-cell long-read transcriptomics","date":"2025-10-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.682832","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.26.615232","title":"Subchondral bone marrow adipose tissue lipolysis regulates bone formation in hand osteoarthritis","date":"2024-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.26.615232","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8679,"output_tokens":1343,"usd":0.023091,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7992,"output_tokens":1951,"usd":0.044367,"stage2_stop_reason":"end_turn"},"total_usd":0.067458,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"CMC1 forms an early cytochrome c oxidase (CIV) assembly intermediate with COX1 and two assembly factors COA3 and COX14 in the mitochondrial intermembrane space. CMC1 stabilizes the COX1-COA3-COX14 complex prior to incorporation of COX4 and COX5a subunits. CMC1 knockout results in normal COX1 synthesis but decreased CIV activity due to instability of newly synthesized COX1, demonstrating that CMC1 regulates COX1 turnover without affecting translation rate.\",\n      \"method\": \"TALEN-mediated CMC1 knockout HEK293T cell line, co-immunoprecipitation of assembly intermediates, metabolic labeling of mitochondrial translation products, CIV activity assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP of assembly complex, KO cell line with defined phenotype, multiple orthogonal methods (translation labeling, activity assay, epistasis with COX10/COX11/SURF1/MITRAC7)\",\n      \"pmids\": [\"28082314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast Cmc1 (ortholog of human CMC1) is a mitochondrial intermembrane space twin CX9C protein required for cytochrome c oxidase biogenesis. Cmc1 physically interacts with Cmc2, and absence of Cmc2 causes a 5-fold increase in Cmc1 accumulation in mitochondrial membranes. CMC1 overexpression does not rescue the respiratory defect of cmc2 mutants, indicating cooperative but non-overlapping functions.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction between Cmc1 and Cmc2), spectrophotometric CIV activity assay, polarographic respiration measurement, genetic complementation/overexpression experiments in yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, enzymatic activity assays, genetic epistasis, conservation validated in C. elegans knockdown\",\n      \"pmids\": [\"20220131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CMC1 (yeast ortholog) is imported into the mitochondrial intermembrane space via the Mia40-Erv1 oxidative folding pathway. CMC1 forms a stable intermediate with Mia40 and is released in the presence of Erv1. All three proteins (Cmc1, Mia40, Erv1) form a ternary complex in mitochondria. Efficient oxidative folding of Cmc1 requires both Erv1 and Mia40 together, preventing non-native disulfide bond formation.\",\n      \"method\": \"In vitro oxidative folding assay, in organello import assay, co-immunoprecipitation of ternary complex (Cmc1-Mia40-Erv1)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of import/folding pathway combined with in organello co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22767599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CMC1 acts as a positive regulator of CD8+ T cell activation and terminal differentiation. Loss of Cmc1 inhibits CD8+ T cell exhaustion and promotes differentiation into metabolically quiescent memory-like cells with increased tolerance to cell death. Environmental lactate enhances CMC1 expression by inducing USP7-mediated stabilization and de-ubiquitination of CMC1 protein, linking the lactate-enriched tumor microenvironment to CD8+ T cell dysfunction via CMC1.\",\n      \"method\": \"Cmc1 knockout mice, in vitro T cell culture system, B16-OVA tumor model, mechanistic study of USP7-mediated de-ubiquitination of CMC1\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype in vivo and in vitro, USP7-CMC1 interaction described but full biochemical reconstitution not explicitly stated in abstract\",\n      \"pmids\": [\"38659649\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human CMC1 is a mitochondrial intermembrane space twin CX9C protein that is imported via the Mia40-Erv1 oxidative folding pathway, where it forms an early cytochrome c oxidase assembly intermediate with COX1, COA3, and COX14 to stabilize newly synthesized COX1 prior to subunit incorporation and metallation; additionally, CMC1 expression in CD8+ T cells is stabilized by USP7-mediated de-ubiquitination in response to lactate, where it promotes T cell activation and exhaustion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CMC1 is a mitochondrial intermembrane space twin CX9C protein that functions in the biogenesis of cytochrome c oxidase (complex IV) [#0, #1]. It is imported into the intermembrane space and oxidatively folded through the Mia40-Erv1 disulfide relay, forming a stable Cmc1-Mia40 intermediate that is resolved by Erv1, with both factors together required to prevent non-native disulfide bond formation [#2]. Within complex IV assembly, CMC1 forms an early intermediate with newly synthesized COX1 and the assembly factors COA3 and COX14, stabilizing the COX1-COA3-COX14 module prior to incorporation of COX4 and COX5a; loss of CMC1 does not affect COX1 translation rate but accelerates COX1 turnover and lowers complex IV activity, establishing CMC1 as a stabilizer of nascent COX1 [#0]. In yeast it cooperates with the partner protein Cmc2 in a non-redundant manner [#1]. Beyond its mitochondrial role, CMC1 acts as a positive regulator of CD8+ T cell activation and terminal differentiation, where USP7-mediated de-ubiquitination stabilizes CMC1 in response to environmental lactate, linking the lactate-rich tumor microenvironment to CD8+ T cell exhaustion [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that CMC1 is an intermembrane space twin CX9C protein required for cytochrome c oxidase biogenesis and that it acts in cooperation with a partner protein, defining its compartment and functional category.\",\n      \"evidence\": \"Co-immunoprecipitation, spectrophotometric CIV activity and respiration assays, and genetic complementation in yeast, with conservation validated in C. elegans knockdown\",\n      \"pmids\": [\"20220131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate/client of Cmc1 within CIV assembly not yet defined\", \"Mechanism of cooperation with Cmc2 unresolved\", \"Human ortholog not yet characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how CMC1 reaches and folds in the intermembrane space, showing it is a Mia40-Erv1 oxidative folding substrate that transits a ternary import intermediate.\",\n      \"evidence\": \"In vitro oxidative folding assay, in organello import, and co-IP of the Cmc1-Mia40-Erv1 ternary complex in yeast\",\n      \"pmids\": [\"22767599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which cysteines form the functional disulfides not mapped\", \"Does folding state gate CIV assembly function unclear\", \"Human import not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the precise role of human CMC1 in complex IV assembly, showing it stabilizes the early COX1-COA3-COX14 intermediate and protects nascent COX1 from degradation rather than affecting its synthesis.\",\n      \"evidence\": \"TALEN CMC1 knockout HEK293T cells, co-IP of assembly intermediates, metabolic labeling of mitochondrial translation, and CIV activity assays\",\n      \"pmids\": [\"28082314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of COX1 stabilization not determined\", \"How CMC1 is released as assembly proceeds unknown\", \"Link to COX1 metallation not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended CMC1 beyond mitochondrial assembly to immune regulation, showing its lactate- and USP7-controlled stability drives CD8+ T cell activation and exhaustion.\",\n      \"evidence\": \"Cmc1 knockout mice, in vitro T cell culture, B16-OVA tumor model, and study of USP7-mediated de-ubiquitination\",\n      \"pmids\": [\"38659649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full biochemical reconstitution of the USP7-CMC1 interaction not established\", \"Whether the immune phenotype derives from CMC1's CIV assembly role or a distinct function unclear\", \"Ubiquitination sites on CMC1 not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CMC1's mitochondrial complex IV assembly activity mechanistically connects to its regulation of CD8+ T cell differentiation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CMC1 in the COX1 assembly intermediate\", \"Metabolic link between CIV function and T cell fate not defined\", \"Whether USP7 acts on the mitochondrial pool of CMC1 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"COX1-COA3-COX14 complex IV assembly intermediate\"],\n    \"partners\": [\"COX1\", \"COA3\", \"COX14\", \"CMC2\", \"MIA40\", \"ERV1\", \"USP7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}