{"gene":"COA1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2007,"finding":"Coa1 (YIL157c) is a novel assembly factor for cytochrome c oxidase (complex IV) in yeast that cooperates with Shy1; Coa1 is required for formation of early complex IV subcomplexes that serve as assembly intermediates, and its loss prevents Shy1-associated subcomplexes from forming.","method":"Genetic analysis (coa1∆ deletion), co-immunoprecipitation, blue-native PAGE to detect assembly intermediates","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and assembly intermediate detection in a single lab with multiple orthogonal methods","pmids":["17882259"],"is_preprint":false},{"year":2010,"finding":"Coa1 binding to the Mss51–Cox14–Coa3–Cox1 complex is essential for full inactivation of Mss51 (trapping it in the latent, translation-resting state), thereby coupling Cox1 translational regulation to cytochrome c oxidase assembly in a negative feedback loop.","method":"Co-immunoprecipitation of assembly intermediates, pulse-labeling of mitochondrial translation products, genetic deletion of COA1/COA3/COX14","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs and pulse-labeling, single lab, consistent with prior work","pmids":["20876281"],"is_preprint":false},{"year":2008,"finding":"Coa2 was identified as a suppressor of coa1∆ respiratory deficiency, placing Coa1 upstream of Coa2 in Cox1 maturation; Coa1 and Shy1 function at an early step in Cox1 maturation, while Coa2 acts downstream at the Shy1-related heme a3 insertion step.","method":"Genetic suppressor screen (overexpression of COA2 suppresses coa1∆), respiratory growth assays, epistasis analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with clear pathway placement, single lab","pmids":["18541668"],"is_preprint":false},{"year":2010,"finding":"The gain-of-function Cox10 N196K suppressor allele restores respiration in coa2∆ cells but lacks suppressor activity for coa1∆ and shy1∆ cells, demonstrating that Coa1's role in Cox1 maturation is distinct from and upstream of the Cox10-mediated heme a addition step.","method":"Genetic epistasis — allele-specific suppression analysis using mutant Cox10 in coa1∆, coa2∆, shy1∆ backgrounds","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific epistasis in multiple genetic backgrounds, single lab","pmids":["19841065"],"is_preprint":false},{"year":2016,"finding":"The I101F Cox1 gain-of-function suppressor mutation restores respiration in cox23∆ cells but fails to suppress respiratory deficiency in cells lacking Coa1, Cox14, Coa2, Shy1, Cox17, or Cox19, demonstrating that Coa1 is specifically required for Cox1 maturation and cannot be bypassed by this Cox1 allele.","method":"Genetic epistasis — mitochondrial Cox1 suppressor mutation tested against panel of CcO assembly factor deletions including coa1∆","journal":"Microbial cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis across multiple assembly factors, single lab","pmids":["28357365"],"is_preprint":false},{"year":2019,"finding":"MITRAC15/COA1 is required for translation of the mitochondrial complex I subunit ND2; MITRAC15 is a constituent of a ribosome–nascent chain complex during ND2 translation, and chemical crosslinking shows that the ND2-specific assembly factor ACAD9 binds the ND2 C-terminus downstream of MITRAC15, placing MITRAC15 co-translationally at the ribosome exit tunnel.","method":"MITRAC15 knockout cell lines, mitochondrial translation pulse-labeling, ribosome sedimentation/co-fractionation, chemical crosslinking mass spectrometry","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — KO with specific translational phenotype, ribosome-nascent chain biochemistry, and chemical crosslinking in one rigorous study","pmids":["31721420"],"is_preprint":false},{"year":2020,"finding":"COA1/MITRAC15 is a bona fide component of the mitochondrial complex I intermediate assembly (MCIA) complex (alongside NDUFAF1, ECSIT, ACAD9, and TMEM126B); COA1 loss causes MCIA complex instability and reduced complex I assembly, and COA1 enriches with newly translated ND2.","method":"CRISPR/Cas9 knockout of COA1 in human cells, blue-native PAGE, co-immunoprecipitation/mass spectrometry of MCIA complex components, mitochondrial translation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO with defined complex I assembly phenotype, reciprocal co-IP/MS, multiple orthogonal methods in one study","pmids":["32320651"],"is_preprint":false},{"year":2021,"finding":"COA1/MITRAC15 promotes mitochondrial translation (chaperone-like role in OXPHOS biogenesis) and is conditionally dispensable in species/lineages that predominantly rely on glycolytic rather than oxidative muscle fibers; gene-disrupting mutations have independently accumulated in cheetah, galliform birds, and rodents.","method":"Comparative genomics, genome re-sequencing of multiple species, evolutionary analysis of COA1 gene structure","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational/evolutionary analysis only, no direct biochemical experiment on the protein","pmids":["34952909"],"is_preprint":false}],"current_model":"COA1/MITRAC15 is a mitochondrial assembly factor that acts at the ribosome exit tunnel as part of the MCIA complex (with NDUFAF1, ECSIT, ACAD9, TMEM126B) to promote co-translational assembly of the ND2-module of complex I, and in yeast also functions at an early Cox1 maturation step where it helps sequester the translational activator Mss51 into a latent complex with Cox14, Coa3, and newly synthesized Cox1, thereby coupling Cox1 translation to cytochrome c oxidase assembly."},"narrative":{"mechanistic_narrative":"COA1 (MITRAC15) is a mitochondrial respiratory-chain assembly factor with conserved but functionally divergent roles in the biogenesis of cytochrome c oxidase (complex IV) in yeast and complex I in humans [PMID:17882259, PMID:32320651]. In yeast, Coa1 cooperates with Shy1 at an early step of Cox1 maturation, where it is required for the formation of early complex IV subcomplexes and acts upstream of the Coa2-dependent, Cox10-mediated heme a insertion step [PMID:17882259, PMID:18541668, PMID:19841065]. Mechanistically, Coa1 binding to the Mss51–Cox14–Coa3–Cox1 intermediate is essential for trapping the translational activator Mss51 in its latent, translation-resting state, thereby coupling Cox1 translation to downstream cytochrome c oxidase assembly through a negative feedback loop [PMID:20876281]. Genetic epistasis with gain-of-function Cox1 alleles confirms that Coa1 is specifically and non-bypassably required for Cox1 maturation [PMID:28357365]. In human cells, COA1/MITRAC15 acts co-translationally at the mitochondrial ribosome exit tunnel as a component of a ribosome–nascent chain complex during translation of the complex I subunit ND2, handing the nascent chain to the ND2-specific assembly factor ACAD9 [PMID:31721420]. COA1 is a bona fide subunit of the mitochondrial complex I intermediate assembly (MCIA) complex with NDUFAF1, ECSIT, ACAD9, and TMEM126B, and its loss destabilizes the MCIA complex and impairs complex I assembly [PMID:32320651].","teleology":[{"year":2007,"claim":"Established COA1 as a novel complex IV assembly factor, defining where it acts: an early step required for formation of Shy1-associated Cox1 assembly intermediates.","evidence":"coa1∆ deletion with co-immunoprecipitation and blue-native PAGE detection of assembly intermediates in yeast","pmids":["17882259"],"confidence":"Medium","gaps":["Molecular mechanism by which Coa1 promotes subcomplex formation not defined","Direct binding partners within the intermediate not resolved"]},{"year":2008,"claim":"Ordered Coa1 within the Cox1 maturation pathway by genetic epistasis, placing it upstream of Coa2 and the heme a3 insertion step.","evidence":"overexpression suppressor screen (COA2 suppresses coa1∆), respiratory growth and epistasis analysis in yeast","pmids":["18541668"],"confidence":"Medium","gaps":["Biochemical step catalyzed or facilitated by Coa1 unknown","Whether Coa1 and Shy1 act in the same or parallel substeps unresolved"]},{"year":2010,"claim":"Defined Coa1's regulatory function in coupling Cox1 translation to assembly by showing it traps the translational activator Mss51 in a latent state.","evidence":"co-IP of assembly intermediates, pulse-labeling of mitochondrial translation, and COA1/COA3/COX14 deletions in yeast","pmids":["20876281"],"confidence":"Medium","gaps":["Structural basis of Mss51 sequestration not determined","Stoichiometry and dynamics of the Mss51–Cox14–Coa3–Cox1 intermediate not defined"]},{"year":2010,"claim":"Distinguished Coa1's step from the Cox10 heme a addition step using allele-specific suppression, confirming Coa1 acts upstream and independently.","evidence":"allele-specific epistasis with gain-of-function Cox10 N196K in coa1∆, coa2∆, shy1∆ backgrounds","pmids":["19841065"],"confidence":"Medium","gaps":["Direct molecular interaction of Coa1 with Cox1 not shown","Mechanism remains genetically rather than biochemically defined"]},{"year":2016,"claim":"Reinforced that Coa1 is a specific, non-bypassable requirement for Cox1 maturation distinct from other assembly factors.","evidence":"mitochondrial Cox1 I101F suppressor tested against a panel of CcO assembly factor deletions in yeast","pmids":["28357365"],"confidence":"Medium","gaps":["Why the Cox1 allele cannot bypass Coa1 loss not mechanistically explained"]},{"year":2019,"claim":"Revealed the human function: MITRAC15/COA1 acts co-translationally at the ribosome exit tunnel during ND2 (complex I) synthesis, handing the nascent chain to ACAD9.","evidence":"MITRAC15 knockout cells, mitochondrial translation pulse-labeling, ribosome co-fractionation, and chemical crosslinking mass spectrometry","pmids":["31721420"],"confidence":"High","gaps":["Direct structural contact of MITRAC15 with the ribosome or nascent ND2 not visualized","How MITRAC15 recognizes the ND2 nascent chain unknown"]},{"year":2020,"claim":"Established COA1 as a stable subunit of the MCIA complex whose loss destabilizes the complex and impairs complex I assembly.","evidence":"CRISPR/Cas9 COA1 knockout in human cells, blue-native PAGE, co-IP/MS of MCIA components, and translation assays","pmids":["32320651"],"confidence":"High","gaps":["Structural arrangement of COA1 within MCIA not resolved","Whether the yeast Cox1 and human ND2 roles share a conserved biochemical mechanism unaddressed"]},{"year":2021,"claim":"Comparative genomics linked COA1 function to OXPHOS demand, showing it is conditionally dispensable in glycolysis-reliant lineages.","evidence":"comparative genomics and genome re-sequencing across cheetah, galliform birds, and rodents","pmids":["34952909"],"confidence":"Low","gaps":["Computational/evolutionary inference only, no direct biochemical experiment on the protein","Physiological consequences of COA1 loss in these lineages not experimentally tested"]},{"year":null,"claim":"Whether the yeast Cox1/complex IV role and the human ND2/complex I role of COA1 reflect a single conserved biochemical mechanism or lineage-specific repurposing remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of COA1 in either complex","No cross-species functional complementation reported","Direct substrate-recognition mechanism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,5,6]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5]}],"complexes":["MCIA complex","Mss51–Cox14–Coa3–Cox1 intermediate"],"partners":["SHY1","MSS51","COX14","COA3","ACAD9","NDUFAF1","ECSIT","TMEM126B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZY4","full_name":"Cytochrome c oxidase assembly factor 1 homolog","aliases":["Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 15 kDa"],"length_aa":146,"mass_kda":16.7,"function":"Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. Required for assembly of mitochondrial respiratory chain complex I and complex IV (PubMed:23260140). As part of the MCIA complex, required for efficient assembly of the mitochondrial complex I (PubMed:32320651)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9GZY4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COA1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COA1","total_profiled":1310},"omim":[{"mim_id":"615180","title":"TRANSLOCASE OF INNER MITOCHONDRIAL MEMBRANE 21; TIMM21","url":"https://www.omim.org/entry/615180"},{"mim_id":"614772","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR 6; COA6","url":"https://www.omim.org/entry/614772"},{"mim_id":"614769","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR 1; COA1","url":"https://www.omim.org/entry/614769"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COA1"},"hgnc":{"alias_symbol":["FLJ10803","MITRAC15"],"prev_symbol":["C7orf44"]},"alphafold":{"accession":"Q9GZY4","domains":[{"cath_id":"3.10.450.320","chopping":"45-133","consensus_level":"high","plddt":95.7543,"start":45,"end":133},{"cath_id":"1.20.5","chopping":"13-43","consensus_level":"medium","plddt":90.5358,"start":13,"end":43}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZY4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZY4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZY4-F1-predicted_aligned_error_v6.png","plddt_mean":88.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COA1","jax_strain_url":"https://www.jax.org/strain/search?query=COA1"},"sequence":{"accession":"Q9GZY4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZY4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZY4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZY4"}},"corpus_meta":[{"pmid":"17882259","id":"PMC_17882259","title":"Shy1 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of Complex I.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32320651","citation_count":85,"is_preprint":false},{"pmid":"18541668","id":"PMC_18541668","title":"Coa2 is an assembly factor for yeast cytochrome c oxidase biogenesis that facilitates the maturation of Cox1.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18541668","citation_count":42,"is_preprint":false},{"pmid":"31396953","id":"PMC_31396953","title":"CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31396953","citation_count":40,"is_preprint":false},{"pmid":"31721420","id":"PMC_31721420","title":"MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome-nascent chain complex.","date":"2019","source":"EMBO 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blue-native PAGE to detect assembly intermediates\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and assembly intermediate detection in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17882259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Coa1 binding to the Mss51–Cox14–Coa3–Cox1 complex is essential for full inactivation of Mss51 (trapping it in the latent, translation-resting state), thereby coupling Cox1 translational regulation to cytochrome c oxidase assembly in a negative feedback loop.\",\n      \"method\": \"Co-immunoprecipitation of assembly intermediates, pulse-labeling of mitochondrial translation products, genetic deletion of COA1/COA3/COX14\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs and pulse-labeling, single lab, consistent with prior work\",\n      \"pmids\": [\"20876281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Coa2 was identified as a suppressor of coa1∆ respiratory deficiency, placing Coa1 upstream of Coa2 in Cox1 maturation; Coa1 and Shy1 function at an early step in Cox1 maturation, while Coa2 acts downstream at the Shy1-related heme a3 insertion step.\",\n      \"method\": \"Genetic suppressor screen (overexpression of COA2 suppresses coa1∆), respiratory growth assays, epistasis analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with clear pathway placement, single lab\",\n      \"pmids\": [\"18541668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The gain-of-function Cox10 N196K suppressor allele restores respiration in coa2∆ cells but lacks suppressor activity for coa1∆ and shy1∆ cells, demonstrating that Coa1's role in Cox1 maturation is distinct from and upstream of the Cox10-mediated heme a addition step.\",\n      \"method\": \"Genetic epistasis — allele-specific suppression analysis using mutant Cox10 in coa1∆, coa2∆, shy1∆ backgrounds\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific epistasis in multiple genetic backgrounds, single lab\",\n      \"pmids\": [\"19841065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The I101F Cox1 gain-of-function suppressor mutation restores respiration in cox23∆ cells but fails to suppress respiratory deficiency in cells lacking Coa1, Cox14, Coa2, Shy1, Cox17, or Cox19, demonstrating that Coa1 is specifically required for Cox1 maturation and cannot be bypassed by this Cox1 allele.\",\n      \"method\": \"Genetic epistasis — mitochondrial Cox1 suppressor mutation tested against panel of CcO assembly factor deletions including coa1∆\",\n      \"journal\": \"Microbial cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis across multiple assembly factors, single lab\",\n      \"pmids\": [\"28357365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MITRAC15/COA1 is required for translation of the mitochondrial complex I subunit ND2; MITRAC15 is a constituent of a ribosome–nascent chain complex during ND2 translation, and chemical crosslinking shows that the ND2-specific assembly factor ACAD9 binds the ND2 C-terminus downstream of MITRAC15, placing MITRAC15 co-translationally at the ribosome exit tunnel.\",\n      \"method\": \"MITRAC15 knockout cell lines, mitochondrial translation pulse-labeling, ribosome sedimentation/co-fractionation, chemical crosslinking mass spectrometry\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — KO with specific translational phenotype, ribosome-nascent chain biochemistry, and chemical crosslinking in one rigorous study\",\n      \"pmids\": [\"31721420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"COA1/MITRAC15 is a bona fide component of the mitochondrial complex I intermediate assembly (MCIA) complex (alongside NDUFAF1, ECSIT, ACAD9, and TMEM126B); COA1 loss causes MCIA complex instability and reduced complex I assembly, and COA1 enriches with newly translated ND2.\",\n      \"method\": \"CRISPR/Cas9 knockout of COA1 in human cells, blue-native PAGE, co-immunoprecipitation/mass spectrometry of MCIA complex components, mitochondrial translation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined complex I assembly phenotype, reciprocal co-IP/MS, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32320651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COA1/MITRAC15 promotes mitochondrial translation (chaperone-like role in OXPHOS biogenesis) and is conditionally dispensable in species/lineages that predominantly rely on glycolytic rather than oxidative muscle fibers; gene-disrupting mutations have independently accumulated in cheetah, galliform birds, and rodents.\",\n      \"method\": \"Comparative genomics, genome re-sequencing of multiple species, evolutionary analysis of COA1 gene structure\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational/evolutionary analysis only, no direct biochemical experiment on the protein\",\n      \"pmids\": [\"34952909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COA1/MITRAC15 is a mitochondrial assembly factor that acts at the ribosome exit tunnel as part of the MCIA complex (with NDUFAF1, ECSIT, ACAD9, TMEM126B) to promote co-translational assembly of the ND2-module of complex I, and in yeast also functions at an early Cox1 maturation step where it helps sequester the translational activator Mss51 into a latent complex with Cox14, Coa3, and newly synthesized Cox1, thereby coupling Cox1 translation to cytochrome c oxidase assembly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COA1 (MITRAC15) is a mitochondrial respiratory-chain assembly factor with conserved but functionally divergent roles in the biogenesis of cytochrome c oxidase (complex IV) in yeast and complex I in humans [#0, #6]. In yeast, Coa1 cooperates with Shy1 at an early step of Cox1 maturation, where it is required for the formation of early complex IV subcomplexes and acts upstream of the Coa2-dependent, Cox10-mediated heme a insertion step [#0, #2, #3]. Mechanistically, Coa1 binding to the Mss51\\u2013Cox14\\u2013Coa3\\u2013Cox1 intermediate is essential for trapping the translational activator Mss51 in its latent, translation-resting state, thereby coupling Cox1 translation to downstream cytochrome c oxidase assembly through a negative feedback loop [#1]. Genetic epistasis with gain-of-function Cox1 alleles confirms that Coa1 is specifically and non-bypassably required for Cox1 maturation [#4]. In human cells, COA1/MITRAC15 acts co-translationally at the mitochondrial ribosome exit tunnel as a component of a ribosome\\u2013nascent chain complex during translation of the complex I subunit ND2, handing the nascent chain to the ND2-specific assembly factor ACAD9 [#5]. COA1 is a bona fide subunit of the mitochondrial complex I intermediate assembly (MCIA) complex with NDUFAF1, ECSIT, ACAD9, and TMEM126B, and its loss destabilizes the MCIA complex and impairs complex I assembly [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established COA1 as a novel complex IV assembly factor, defining where it acts: an early step required for formation of Shy1-associated Cox1 assembly intermediates.\",\n      \"evidence\": \"coa1\\u2206 deletion with co-immunoprecipitation and blue-native PAGE detection of assembly intermediates in yeast\",\n      \"pmids\": [\"17882259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which Coa1 promotes subcomplex formation not defined\", \"Direct binding partners within the intermediate not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Ordered Coa1 within the Cox1 maturation pathway by genetic epistasis, placing it upstream of Coa2 and the heme a3 insertion step.\",\n      \"evidence\": \"overexpression suppressor screen (COA2 suppresses coa1\\u2206), respiratory growth and epistasis analysis in yeast\",\n      \"pmids\": [\"18541668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical step catalyzed or facilitated by Coa1 unknown\", \"Whether Coa1 and Shy1 act in the same or parallel substeps unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined Coa1's regulatory function in coupling Cox1 translation to assembly by showing it traps the translational activator Mss51 in a latent state.\",\n      \"evidence\": \"co-IP of assembly intermediates, pulse-labeling of mitochondrial translation, and COA1/COA3/COX14 deletions in yeast\",\n      \"pmids\": [\"20876281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of Mss51 sequestration not determined\", \"Stoichiometry and dynamics of the Mss51\\u2013Cox14\\u2013Coa3\\u2013Cox1 intermediate not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Distinguished Coa1's step from the Cox10 heme a addition step using allele-specific suppression, confirming Coa1 acts upstream and independently.\",\n      \"evidence\": \"allele-specific epistasis with gain-of-function Cox10 N196K in coa1\\u2206, coa2\\u2206, shy1\\u2206 backgrounds\",\n      \"pmids\": [\"19841065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular interaction of Coa1 with Cox1 not shown\", \"Mechanism remains genetically rather than biochemically defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reinforced that Coa1 is a specific, non-bypassable requirement for Cox1 maturation distinct from other assembly factors.\",\n      \"evidence\": \"mitochondrial Cox1 I101F suppressor tested against a panel of CcO assembly factor deletions in yeast\",\n      \"pmids\": [\"28357365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why the Cox1 allele cannot bypass Coa1 loss not mechanistically explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed the human function: MITRAC15/COA1 acts co-translationally at the ribosome exit tunnel during ND2 (complex I) synthesis, handing the nascent chain to ACAD9.\",\n      \"evidence\": \"MITRAC15 knockout cells, mitochondrial translation pulse-labeling, ribosome co-fractionation, and chemical crosslinking mass spectrometry\",\n      \"pmids\": [\"31721420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural contact of MITRAC15 with the ribosome or nascent ND2 not visualized\", \"How MITRAC15 recognizes the ND2 nascent chain unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established COA1 as a stable subunit of the MCIA complex whose loss destabilizes the complex and impairs complex I assembly.\",\n      \"evidence\": \"CRISPR/Cas9 COA1 knockout in human cells, blue-native PAGE, co-IP/MS of MCIA components, and translation assays\",\n      \"pmids\": [\"32320651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural arrangement of COA1 within MCIA not resolved\", \"Whether the yeast Cox1 and human ND2 roles share a conserved biochemical mechanism unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Comparative genomics linked COA1 function to OXPHOS demand, showing it is conditionally dispensable in glycolysis-reliant lineages.\",\n      \"evidence\": \"comparative genomics and genome re-sequencing across cheetah, galliform birds, and rodents\",\n      \"pmids\": [\"34952909\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational/evolutionary inference only, no direct biochemical experiment on the protein\", \"Physiological consequences of COA1 loss in these lineages not experimentally tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the yeast Cox1/complex IV role and the human ND2/complex I role of COA1 reflect a single conserved biochemical mechanism or lineage-specific repurposing remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of COA1 in either complex\", \"No cross-species functional complementation reported\", \"Direct substrate-recognition mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"MCIA complex\",\n      \"Mss51\\u2013Cox14\\u2013Coa3\\u2013Cox1 intermediate\"\n    ],\n    \"partners\": [\n      \"SHY1\",\n      \"MSS51\",\n      \"COX14\",\n      \"COA3\",\n      \"ACAD9\",\n      \"NDUFAF1\",\n      \"ECSIT\",\n      \"TMEM126B\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}