{"gene":"COX10","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1990,"finding":"COX10 encodes a nuclear gene product required for cytochrome oxidase assembly in yeast (S. cerevisiae); its product acts at a post-translational stage of enzyme assembly. The protein has a hydrophilic N-terminal domain and a hydrophobic C-terminal region with nine predicted transmembrane segments, and shares homology with ORF1 of the Paracoccus denitrificans cytochrome oxidase operon.","method":"Genetic complementation, nucleotide sequencing, hydrophobicity analysis, cytochrome oxidase subunit analysis in mutant yeast","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — original cloning with functional complementation and sequence-based structural analysis, foundational paper replicated across subsequent studies","pmids":["2167310"],"is_preprint":false},{"year":1993,"finding":"The yeast COX10 protein is required for heme A synthesis; specifically, it catalyzes the conversion of protoheme to heme O (farnesylation step), establishing its role as a farnesyl transferase in the heme A biosynthetic pathway.","method":"Heme constituent analysis in cox10 mutant yeast, biochemical chromatographic characterization","journal":"Biochemistry and molecular biology international","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical demonstration of enzymatic function in yeast ortholog, corroborated by multiple subsequent studies","pmids":["8118433"],"is_preprint":false},{"year":1994,"finding":"Human COX10 encodes heme A:farnesyltransferase; the human cDNA was isolated by functional complementation of a yeast cox10 null mutant, confirming orthologous enzymatic function.","method":"Functional complementation of yeast cox10 null mutant with human cDNA library, Southern blot, PCR amplification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — functional complementation directly establishing enzymatic identity across species","pmids":["8078902"],"is_preprint":false},{"year":2000,"finding":"A homozygous missense mutation in human COX10 causes cytochrome c oxidase deficiency; complementation in yeast confirmed that COX10 encodes heme A:farnesyltransferase catalyzing the first step in protoheme-to-heme A conversion, and loss of COX10 function disrupts COX assembly.","method":"Genome-wide linkage mapping, mutation analysis, yeast complementation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — direct complementation assay in yeast confirming pathogenic missense mutation abrogates enzymatic function","pmids":["10767350"],"is_preprint":false},{"year":2003,"finding":"COX10 catalyzes the conversion of protoheme (heme B) to heme O via farnesylation at C2; loss-of-function COX10 mutations reduce heme A content in patient muscle and fibroblasts proportional to reduction in COX enzyme activity and fully assembled enzyme. Retroviral expression of COX10 complements COX deficiency in patient fibroblasts. Missense mutations map to evolutionarily conserved residues in regions shown to have catalytic importance in prokaryotic orthologs.","method":"Retroviral complementation, heme A content measurement in patient mitochondria, microcell-mediated chromosome transfer, mutation analysis with topological modeling","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including complementation, heme content quantification, and structural modeling; replicated across multiple patient cell lines","pmids":["12928484"],"is_preprint":false},{"year":2003,"finding":"In COX10-deficient patient fibroblasts, the COX subassembly containing MTCO1, COX4, and COX5A is absent (while it accumulates in SCO1- and SURF1-deficient cells), indicating that heme A incorporation into MTCO1 by COX10 occurs prior to association of MTCO1 with COX4 and COX5A during COX assembly.","method":"Blue native PAGE immunoblotting of native gel COX subassemblies in patient fibroblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct comparison of assembly intermediates across three genotypes establishes COX10 epistatic position in assembly pathway","pmids":["14607829"],"is_preprint":false},{"year":2004,"finding":"A homozygous mutation in the COX10 start codon causes COX deficiency with Leigh-like disease; overexpression of COX10 protein in patient fibroblasts rescues the defect, and 2D gel electrophoresis showed decreased fully assembled COX without accumulation of partial subcomplexes.","method":"2D gel electrophoresis, western blot, overexpression rescue in patient fibroblasts","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 — direct rescue experiment with multiple complementary analyses","pmids":["15455402"],"is_preprint":false},{"year":2005,"finding":"Conditional knockout of COX10 in skeletal muscle (using Cre-lox under myosin light chain 1f promoter) causes isolated COX deficiency (<5% of control COX activity) and progressive mitochondrial myopathy, demonstrating that COX10-dependent heme A synthesis is required for COX activity and normal muscle function in vivo.","method":"Conditional knockout mouse model (Cre-lox), COX activity assay, muscle force/fatigue measurement, oxidative damage and apoptosis assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean tissue-specific KO with defined phenotypic readout and biochemical quantification","pmids":["16103131"],"is_preprint":false},{"year":2010,"finding":"In yeast, the Coa2 assembly factor stabilizes the oligomeric Cox10 farnesyl transferase complex involved in heme a addition to Cox1. A gain-of-function N196K substitution in Cox10 suppresses the respiratory deficiency of coa2Δ cells, and this suppressor activity depends on Cox10 catalytic function and the presence of Cox15 (the second heme A biosynthetic enzyme). The N196K substitution correlates with stabilization of the high-mass homo-oligomeric Cox10 complex.","method":"Genetic suppressor analysis, respiratory growth assays, yeast genetics (double mutants), complex size analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — epistasis and gain-of-function mutagenesis with multiple orthogonal functional tests","pmids":["19841065"],"is_preprint":false},{"year":2010,"finding":"miR-210 directly targets COX10 mRNA (along with ISCU), reducing COX10 expression under hypoxia, thereby decreasing mitochondrial function and increasing glycolysis and reactive oxygen species generation in cancer cells.","method":"miRNA target identification in cancer cell lines, hypoxia experiments, mitochondrial function assays, ROS measurement","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — COX10 identified as miR-210 target but direct demonstration of 3'UTR binding not extensively detailed; replicated by subsequent independent studies","pmids":["20498629"],"is_preprint":false},{"year":2013,"finding":"COX10 mutations causing amino acid substitutions at conserved residues (Asp336Val and Arg339Trp) result in absence of detectable COX holoenzyme and subassemblies on blue-native gels, reduced MTCO1 on denaturing gels, and low heme aa3 content by absorption spectroscopy, consistent with heme A:farnesyltransferase deficiency. Both mutations were confirmed pathogenic by yeast respiratory deficiency assay.","method":"Blue native PAGE immunoblot, heme absorption spectroscopy, yeast functional assay, protein structural modeling","journal":"JAMA neurology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods plus yeast functional validation","pmids":["24100867"],"is_preprint":false},{"year":2021,"finding":"NK cell-specific deletion of Cox10 (inducible Ncr1-Cox10Δ/Δ mice) impairs antigen-specific Ly49H+ NK cell expansion and memory formation during murine cytomegalovirus infection, while homeostatic proliferation is intact. Cox10-deficient NK cells upregulate glycolysis with increased AMPK and mTOR activation, demonstrating that oxidative phosphorylation (COX10-dependent complex IV activity) is specifically required for antigen-driven NK cell proliferation in vivo.","method":"Conditional KO mouse, viral infection model (MCMV), flow cytometry, metabolic flux assays, in vitro proliferation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — clean cell-type-specific KO with defined immunological and metabolic phenotype and multiple orthogonal readouts","pmids":["34077722"],"is_preprint":false},{"year":2024,"finding":"Mild therapeutic hypothermia upregulates O-GlcNAcylation of COX10 protein (mediated by OGT), which improves mitochondrial function and reduces ROS in myocardial ischemia-reperfusion injury. Pharmacological inhibition of OGT (ALX) reduces COX10 O-GlcNAcylation and abolishes the cardioprotective effect, while OGA inhibition enhances it.","method":"Langendorff isolated heart model, hypoxia/reoxygenation cell model, immunoprecipitation, western blot, OGT/OGA pharmacological modulation, immunofluorescence","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct demonstration of post-translational modification with functional consequence using pharmacological tools, but writer/site not mapped at residue level","pmids":["38778315"],"is_preprint":false},{"year":2024,"finding":"25 human COX10 missense variants were expressed in yeast and phenotyped; 11 variants supported ~half or more wild-type cytochrome c oxidase activity and growth on non-fermentable carbon sources, while the remainder showed severely reduced COX activity, directly correlating COX10 variant status with enzymatic function.","method":"Heterologous expression of human COX10 variants in yeast, COX activity assay, non-fermentable carbon source growth assay","journal":"BMC research notes","confidence":"High","confidence_rationale":"Tier 1 — systematic in vivo enzymatic functional assay for 25 variants with direct COX activity measurement","pmids":["39152498"],"is_preprint":false}],"current_model":"COX10 encodes a mitochondrial heme A:farnesyltransferase that catalyzes the first step in heme A biosynthesis—farnesylation of protoheme (heme B) to heme O—which is required for heme A incorporation into the COX1 subunit of cytochrome c oxidase (Complex IV) prior to association with COX4/COX5A, thereby enabling full COX assembly and oxidative phosphorylation; loss of COX10 causes severe COX deficiency and progressive mitochondrial disease, and COX10 activity is post-translationally regulated by O-GlcNAcylation and transcriptionally suppressed by hypoxia-induced miR-210."},"narrative":{"teleology":[{"year":1990,"claim":"Identification of COX10 as a nuclear gene required post-translationally for cytochrome oxidase assembly established that COX biogenesis depends on dedicated nuclear-encoded factors beyond the structural subunits themselves.","evidence":"Genetic complementation of respiratory-deficient yeast mutants, nucleotide sequencing, and topological prediction of nine transmembrane segments","pmids":["2167310"],"confidence":"High","gaps":["Enzymatic function not yet determined","Subcellular localization to mitochondrial inner membrane not directly demonstrated","Mammalian ortholog not yet identified"]},{"year":1993,"claim":"Biochemical analysis of heme constituents in cox10 mutant yeast demonstrated that COX10 catalyzes the farnesylation of protoheme to heme O, resolving its enzymatic identity as a heme A:farnesyltransferase.","evidence":"Chromatographic heme analysis in yeast cox10Δ mutants showing absence of heme O and heme A","pmids":["8118433"],"confidence":"High","gaps":["In vitro reconstitution of farnesyltransferase activity not performed","Substrate specificity (farnesyl-PP vs. other isoprenoids) not directly tested"]},{"year":1994,"claim":"Functional complementation of yeast cox10Δ by human COX10 cDNA confirmed cross-species conservation of enzymatic function and enabled study of the human enzyme.","evidence":"Isolation of human cDNA from expression library by yeast complementation, Southern blot confirmation","pmids":["8078902"],"confidence":"High","gaps":["Human enzyme kinetics not characterized","Tissue expression pattern not mapped"]},{"year":2000,"claim":"Discovery of a pathogenic homozygous COX10 missense mutation in a patient with COX deficiency established COX10 as a Mendelian disease gene and linked heme A biosynthesis to human mitochondrial disease.","evidence":"Genome-wide linkage analysis, mutation identification, and yeast complementation assay","pmids":["10767350"],"confidence":"High","gaps":["Genotype-phenotype spectrum not yet defined","Residual enzymatic activity of mutant protein not quantified"]},{"year":2003,"claim":"Quantitative measurements in patient tissues and rescue experiments placed COX10 enzymatic activity upstream of COX1-COX4-COX5A subcomplex formation, defining its position in the assembly pathway and showing that heme A content directly determines COX holoenzyme abundance.","evidence":"Blue native PAGE of assembly intermediates across COX10-, SCO1-, and SURF1-deficient fibroblasts; retroviral complementation; heme A spectroscopic quantification","pmids":["12928484","14607829"],"confidence":"High","gaps":["Direct physical interaction between COX10 and COX1 during heme insertion not demonstrated","Mechanism of heme A transfer to COX1 unknown"]},{"year":2004,"claim":"Identification of a start-codon mutation causing Leigh-like disease expanded the clinical spectrum and confirmed by overexpression rescue that even partial loss of COX10 protein is sufficient to cause severe COX deficiency.","evidence":"2D gel electrophoresis and COX10 overexpression rescue in patient fibroblasts","pmids":["15455402"],"confidence":"High","gaps":["Threshold of residual COX10 activity compatible with health not defined"]},{"year":2005,"claim":"A skeletal-muscle-specific Cox10 knockout mouse demonstrated in vivo that COX10-dependent heme A synthesis is essential for muscle COX activity and normal contractile function, providing an animal model of mitochondrial myopathy.","evidence":"Cre-lox conditional knockout (MLC1f-Cre), COX activity assays, force measurements","pmids":["16103131"],"confidence":"High","gaps":["Whether compensatory metabolic remodeling occurs over time not fully characterized","Cardiac-specific consequences not addressed in this model"]},{"year":2010,"claim":"Genetic suppressor analysis in yeast revealed that COX10 functions as a homo-oligomeric complex stabilized by the Coa2 assembly factor, and that complex integrity is essential for its catalytic activity in heme A biosynthesis.","evidence":"Gain-of-function N196K suppressor of coa2Δ, epistasis with cox15Δ, oligomeric complex size analysis","pmids":["19841065"],"confidence":"High","gaps":["Oligomeric stoichiometry not determined","Whether Coa2-like stabilization occurs in mammalian cells unknown"]},{"year":2010,"claim":"Identification of COX10 mRNA as a direct target of hypoxia-induced miR-210 revealed a transcriptional regulatory axis linking oxygen sensing to mitochondrial electron transport chain remodeling.","evidence":"miRNA target identification in cancer cell lines under hypoxia, mitochondrial function and ROS assays","pmids":["20498629"],"confidence":"Medium","gaps":["Direct 3'UTR reporter validation not extensively detailed","Relative contribution of COX10 versus ISCU suppression to the metabolic phenotype not separated"]},{"year":2021,"claim":"NK cell-specific Cox10 deletion demonstrated that Complex IV-dependent oxidative phosphorylation is dispensable for homeostatic NK cell proliferation but specifically required for antigen-driven clonal expansion and memory formation, assigning COX10 a cell-type-specific immunological role.","evidence":"Ncr1-Cre conditional KO mice, MCMV infection, flow cytometry, metabolic flux analysis","pmids":["34077722"],"confidence":"High","gaps":["Whether the metabolic requirement extends to other lymphocyte populations not tested","Mechanism by which glycolytic compensation fails to support clonal expansion unknown"]},{"year":2024,"claim":"Discovery that O-GlcNAcylation of COX10 protein by OGT enhances mitochondrial function during ischemia-reperfusion established post-translational modification as a regulatory mechanism for COX10 activity in the heart.","evidence":"Langendorff heart model, immunoprecipitation for O-GlcNAc, OGT/OGA pharmacological modulation","pmids":["38778315"],"confidence":"Medium","gaps":["Specific O-GlcNAcylation site(s) on COX10 not mapped","Whether O-GlcNAcylation affects COX10 catalytic activity directly or its stability/oligomerization not distinguished"]},{"year":2024,"claim":"Systematic functional phenotyping of 25 human COX10 missense variants in yeast provided a quantitative genotype-activity map, directly correlating variant-specific COX10 residues with enzymatic output.","evidence":"Heterologous expression in yeast, COX activity measurement, non-fermentable carbon growth assays","pmids":["39152498"],"confidence":"High","gaps":["Activity measurements performed in yeast, not in human cells","Structure-function mapping limited by absence of an atomic-resolution COX10 structure"]},{"year":null,"claim":"No atomic-resolution structure of COX10 exists, the mechanism of heme O transfer from COX10 to COX1 remains undefined, and the mammalian equivalent of the Coa2-dependent oligomeric regulation has not been established.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model at atomic resolution","Heme O handoff mechanism to COX1 unknown","Mammalian COX10 oligomeric state and its regulators uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,3,4,13]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,4,5,7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,4,8]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,6,10]}],"complexes":["COX10 homo-oligomeric complex"],"partners":["COA2","COX15","MT-CO1","OGT"],"other_free_text":[]},"mechanistic_narrative":"COX10 is a mitochondrial inner-membrane heme A:farnesyltransferase that catalyzes the farnesylation of protoheme (heme B) to heme O, the first committed step in heme A biosynthesis required for cytochrome c oxidase (Complex IV) assembly and oxidative phosphorylation [PMID:8118433, PMID:8078902]. Heme A produced through COX10 (and subsequently COX15) is incorporated into the COX1 subunit prior to its association with COX4 and COX5A; in the absence of COX10, neither the COX1-containing subassembly nor the holoenzyme accumulates, resulting in severe isolated Complex IV deficiency [PMID:14607829, PMID:12928484]. COX10 functions as a homo-oligomeric complex stabilized by the assembly factor Coa2, and its activity is post-translationally regulated by O-GlcNAcylation and transcriptionally suppressed under hypoxia via miR-210 [PMID:19841065, PMID:38778315, PMID:20498629]. Loss-of-function mutations in COX10 cause autosomal recessive COX deficiency presenting as Leigh-like syndrome and progressive mitochondrial myopathy, confirmed by complementation rescue in patient fibroblasts and yeast [PMID:10767350, PMID:15455402, PMID:16103131]."},"prefetch_data":{"uniprot":{"accession":"Q12887","full_name":"Protoheme IX farnesyltransferase, mitochondrial","aliases":["Heme O synthase"],"length_aa":443,"mass_kda":48.9,"function":"Converts protoheme IX and farnesyl diphosphate to heme O","subcellular_location":"Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q12887/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COX10","classification":"Not Classified","n_dependent_lines":531,"n_total_lines":1208,"dependency_fraction":0.43956953642384106},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COX10","total_profiled":1310},"omim":[{"mim_id":"619046","title":"MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 3; MC4DN3","url":"https://www.omim.org/entry/619046"},{"mim_id":"604596","title":"F-BOX AND WD REPEAT DOMAIN 10B; FBXW10B","url":"https://www.omim.org/entry/604596"},{"mim_id":"603644","title":"SYNTHESIS OF CYTOCHROME c OXIDASE 1; SCO1","url":"https://www.omim.org/entry/603644"},{"mim_id":"602125","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR COX10; COX10","url":"https://www.omim.org/entry/602125"},{"mim_id":"601097","title":"PERIPHERAL MYELIN PROTEIN 22; PMP22","url":"https://www.omim.org/entry/601097"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":40.5},{"tissue":"tongue","ntpm":41.4}],"url":"https://www.proteinatlas.org/search/COX10"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q12887","domains":[{"cath_id":"1.10.357.140","chopping":"147-305","consensus_level":"medium","plddt":95.227,"start":147,"end":305},{"cath_id":"1.20.120","chopping":"308-432","consensus_level":"medium","plddt":96.2113,"start":308,"end":432}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12887","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12887-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12887-F1-predicted_aligned_error_v6.png","plddt_mean":77.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COX10","jax_strain_url":"https://www.jax.org/strain/search?query=COX10"},"sequence":{"accession":"Q12887","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12887.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12887/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12887"}},"corpus_meta":[{"pmid":"20498629","id":"PMC_20498629","title":"Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20498629","citation_count":335,"is_preprint":false},{"pmid":"10767350","id":"PMC_10767350","title":"A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10767350","citation_count":241,"is_preprint":false},{"pmid":"12928484","id":"PMC_12928484","title":"Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.","date":"2003","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12928484","citation_count":194,"is_preprint":false},{"pmid":"16103131","id":"PMC_16103131","title":"Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16103131","citation_count":140,"is_preprint":false},{"pmid":"2167310","id":"PMC_2167310","title":"COX10 codes for a protein homologous to the ORF1 product of Paracoccus denitrificans and is required for the synthesis of yeast cytochrome oxidase.","date":"1990","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2167310","citation_count":122,"is_preprint":false},{"pmid":"14607829","id":"PMC_14607829","title":"Cytochrome c oxidase subassemblies in fibroblast cultures from patients carrying mutations in COX10, SCO1, or SURF1.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14607829","citation_count":115,"is_preprint":false},{"pmid":"8118433","id":"PMC_8118433","title":"On the functions of the yeast COX10 and COX11 gene 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disrupted during homologous recombination between the 24 kb proximal and distal CMT1A-REPs.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9285799","citation_count":72,"is_preprint":false},{"pmid":"27799210","id":"PMC_27799210","title":"Screening and Characterization of a Non-cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance.","date":"2016","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/27799210","citation_count":62,"is_preprint":false},{"pmid":"15455402","id":"PMC_15455402","title":"Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.","date":"2004","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15455402","citation_count":43,"is_preprint":false},{"pmid":"19841065","id":"PMC_19841065","title":"The role of Coa2 in hemylation of yeast Cox1 revealed by its genetic interaction with Cox10.","date":"2010","source":"Molecular and 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carcinoma.","date":"2023","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/37056821","citation_count":6,"is_preprint":false},{"pmid":"34986861","id":"PMC_34986861","title":"Knockdown of NCK1-AS1 inhibits the development of atherosclerosis by targeting miR-1197/COX10 axis.","date":"2022","source":"Journal of biological engineering","url":"https://pubmed.ncbi.nlm.nih.gov/34986861","citation_count":5,"is_preprint":false},{"pmid":"38244670","id":"PMC_38244670","title":"Long Non-coding RNA COX10-AS1 Promotes Glioma Progression by Competitively Binding miR-1-3p to Regulate ORC6 Expression.","date":"2024","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38244670","citation_count":4,"is_preprint":false},{"pmid":"38846886","id":"PMC_38846886","title":"Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.","date":"2024","source":"Annals of medicine and surgery (2012)","url":"https://pubmed.ncbi.nlm.nih.gov/38846886","citation_count":4,"is_preprint":false},{"pmid":"33180568","id":"PMC_33180568","title":"A Novel COX10 Deletion Polymorphism as a Susceptibility Factor for Sudden Cardiac Death Risk in Chinese Populations.","date":"2020","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33180568","citation_count":4,"is_preprint":false},{"pmid":"36176336","id":"PMC_36176336","title":"Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.","date":"2022","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36176336","citation_count":3,"is_preprint":false},{"pmid":"39152498","id":"PMC_39152498","title":"Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.","date":"2024","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/39152498","citation_count":1,"is_preprint":false},{"pmid":"19694371","id":"PMC_19694371","title":"[Expression of COX10 in human non-obstructive azoospermia testes].","date":"2009","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/19694371","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15549,"output_tokens":3309,"usd":0.048141},"stage2":{"model":"claude-opus-4-6","input_tokens":6698,"output_tokens":2738,"usd":0.15291},"total_usd":0.201051,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"COX10 encodes a nuclear gene product required for cytochrome oxidase assembly in yeast (S. cerevisiae); its product acts at a post-translational stage of enzyme assembly. The protein has a hydrophilic N-terminal domain and a hydrophobic C-terminal region with nine predicted transmembrane segments, and shares homology with ORF1 of the Paracoccus denitrificans cytochrome oxidase operon.\",\n      \"method\": \"Genetic complementation, nucleotide sequencing, hydrophobicity analysis, cytochrome oxidase subunit analysis in mutant yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original cloning with functional complementation and sequence-based structural analysis, foundational paper replicated across subsequent studies\",\n      \"pmids\": [\"2167310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The yeast COX10 protein is required for heme A synthesis; specifically, it catalyzes the conversion of protoheme to heme O (farnesylation step), establishing its role as a farnesyl transferase in the heme A biosynthetic pathway.\",\n      \"method\": \"Heme constituent analysis in cox10 mutant yeast, biochemical chromatographic characterization\",\n      \"journal\": \"Biochemistry and molecular biology international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical demonstration of enzymatic function in yeast ortholog, corroborated by multiple subsequent studies\",\n      \"pmids\": [\"8118433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Human COX10 encodes heme A:farnesyltransferase; the human cDNA was isolated by functional complementation of a yeast cox10 null mutant, confirming orthologous enzymatic function.\",\n      \"method\": \"Functional complementation of yeast cox10 null mutant with human cDNA library, Southern blot, PCR amplification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional complementation directly establishing enzymatic identity across species\",\n      \"pmids\": [\"8078902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A homozygous missense mutation in human COX10 causes cytochrome c oxidase deficiency; complementation in yeast confirmed that COX10 encodes heme A:farnesyltransferase catalyzing the first step in protoheme-to-heme A conversion, and loss of COX10 function disrupts COX assembly.\",\n      \"method\": \"Genome-wide linkage mapping, mutation analysis, yeast complementation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct complementation assay in yeast confirming pathogenic missense mutation abrogates enzymatic function\",\n      \"pmids\": [\"10767350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"COX10 catalyzes the conversion of protoheme (heme B) to heme O via farnesylation at C2; loss-of-function COX10 mutations reduce heme A content in patient muscle and fibroblasts proportional to reduction in COX enzyme activity and fully assembled enzyme. Retroviral expression of COX10 complements COX deficiency in patient fibroblasts. Missense mutations map to evolutionarily conserved residues in regions shown to have catalytic importance in prokaryotic orthologs.\",\n      \"method\": \"Retroviral complementation, heme A content measurement in patient mitochondria, microcell-mediated chromosome transfer, mutation analysis with topological modeling\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including complementation, heme content quantification, and structural modeling; replicated across multiple patient cell lines\",\n      \"pmids\": [\"12928484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In COX10-deficient patient fibroblasts, the COX subassembly containing MTCO1, COX4, and COX5A is absent (while it accumulates in SCO1- and SURF1-deficient cells), indicating that heme A incorporation into MTCO1 by COX10 occurs prior to association of MTCO1 with COX4 and COX5A during COX assembly.\",\n      \"method\": \"Blue native PAGE immunoblotting of native gel COX subassemblies in patient fibroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct comparison of assembly intermediates across three genotypes establishes COX10 epistatic position in assembly pathway\",\n      \"pmids\": [\"14607829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A homozygous mutation in the COX10 start codon causes COX deficiency with Leigh-like disease; overexpression of COX10 protein in patient fibroblasts rescues the defect, and 2D gel electrophoresis showed decreased fully assembled COX without accumulation of partial subcomplexes.\",\n      \"method\": \"2D gel electrophoresis, western blot, overexpression rescue in patient fibroblasts\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct rescue experiment with multiple complementary analyses\",\n      \"pmids\": [\"15455402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Conditional knockout of COX10 in skeletal muscle (using Cre-lox under myosin light chain 1f promoter) causes isolated COX deficiency (<5% of control COX activity) and progressive mitochondrial myopathy, demonstrating that COX10-dependent heme A synthesis is required for COX activity and normal muscle function in vivo.\",\n      \"method\": \"Conditional knockout mouse model (Cre-lox), COX activity assay, muscle force/fatigue measurement, oxidative damage and apoptosis assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KO with defined phenotypic readout and biochemical quantification\",\n      \"pmids\": [\"16103131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In yeast, the Coa2 assembly factor stabilizes the oligomeric Cox10 farnesyl transferase complex involved in heme a addition to Cox1. A gain-of-function N196K substitution in Cox10 suppresses the respiratory deficiency of coa2Δ cells, and this suppressor activity depends on Cox10 catalytic function and the presence of Cox15 (the second heme A biosynthetic enzyme). The N196K substitution correlates with stabilization of the high-mass homo-oligomeric Cox10 complex.\",\n      \"method\": \"Genetic suppressor analysis, respiratory growth assays, yeast genetics (double mutants), complex size analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis and gain-of-function mutagenesis with multiple orthogonal functional tests\",\n      \"pmids\": [\"19841065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-210 directly targets COX10 mRNA (along with ISCU), reducing COX10 expression under hypoxia, thereby decreasing mitochondrial function and increasing glycolysis and reactive oxygen species generation in cancer cells.\",\n      \"method\": \"miRNA target identification in cancer cell lines, hypoxia experiments, mitochondrial function assays, ROS measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — COX10 identified as miR-210 target but direct demonstration of 3'UTR binding not extensively detailed; replicated by subsequent independent studies\",\n      \"pmids\": [\"20498629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COX10 mutations causing amino acid substitutions at conserved residues (Asp336Val and Arg339Trp) result in absence of detectable COX holoenzyme and subassemblies on blue-native gels, reduced MTCO1 on denaturing gels, and low heme aa3 content by absorption spectroscopy, consistent with heme A:farnesyltransferase deficiency. Both mutations were confirmed pathogenic by yeast respiratory deficiency assay.\",\n      \"method\": \"Blue native PAGE immunoblot, heme absorption spectroscopy, yeast functional assay, protein structural modeling\",\n      \"journal\": \"JAMA neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods plus yeast functional validation\",\n      \"pmids\": [\"24100867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NK cell-specific deletion of Cox10 (inducible Ncr1-Cox10Δ/Δ mice) impairs antigen-specific Ly49H+ NK cell expansion and memory formation during murine cytomegalovirus infection, while homeostatic proliferation is intact. Cox10-deficient NK cells upregulate glycolysis with increased AMPK and mTOR activation, demonstrating that oxidative phosphorylation (COX10-dependent complex IV activity) is specifically required for antigen-driven NK cell proliferation in vivo.\",\n      \"method\": \"Conditional KO mouse, viral infection model (MCMV), flow cytometry, metabolic flux assays, in vitro proliferation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean cell-type-specific KO with defined immunological and metabolic phenotype and multiple orthogonal readouts\",\n      \"pmids\": [\"34077722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mild therapeutic hypothermia upregulates O-GlcNAcylation of COX10 protein (mediated by OGT), which improves mitochondrial function and reduces ROS in myocardial ischemia-reperfusion injury. Pharmacological inhibition of OGT (ALX) reduces COX10 O-GlcNAcylation and abolishes the cardioprotective effect, while OGA inhibition enhances it.\",\n      \"method\": \"Langendorff isolated heart model, hypoxia/reoxygenation cell model, immunoprecipitation, western blot, OGT/OGA pharmacological modulation, immunofluorescence\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct demonstration of post-translational modification with functional consequence using pharmacological tools, but writer/site not mapped at residue level\",\n      \"pmids\": [\"38778315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"25 human COX10 missense variants were expressed in yeast and phenotyped; 11 variants supported ~half or more wild-type cytochrome c oxidase activity and growth on non-fermentable carbon sources, while the remainder showed severely reduced COX activity, directly correlating COX10 variant status with enzymatic function.\",\n      \"method\": \"Heterologous expression of human COX10 variants in yeast, COX activity assay, non-fermentable carbon source growth assay\",\n      \"journal\": \"BMC research notes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic in vivo enzymatic functional assay for 25 variants with direct COX activity measurement\",\n      \"pmids\": [\"39152498\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COX10 encodes a mitochondrial heme A:farnesyltransferase that catalyzes the first step in heme A biosynthesis—farnesylation of protoheme (heme B) to heme O—which is required for heme A incorporation into the COX1 subunit of cytochrome c oxidase (Complex IV) prior to association with COX4/COX5A, thereby enabling full COX assembly and oxidative phosphorylation; loss of COX10 causes severe COX deficiency and progressive mitochondrial disease, and COX10 activity is post-translationally regulated by O-GlcNAcylation and transcriptionally suppressed by hypoxia-induced miR-210.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COX10 is a mitochondrial inner-membrane heme A:farnesyltransferase that catalyzes the farnesylation of protoheme (heme B) to heme O, the first committed step in heme A biosynthesis required for cytochrome c oxidase (Complex IV) assembly and oxidative phosphorylation [PMID:8118433, PMID:8078902]. Heme A produced through COX10 (and subsequently COX15) is incorporated into the COX1 subunit prior to its association with COX4 and COX5A; in the absence of COX10, neither the COX1-containing subassembly nor the holoenzyme accumulates, resulting in severe isolated Complex IV deficiency [PMID:14607829, PMID:12928484]. COX10 functions as a homo-oligomeric complex stabilized by the assembly factor Coa2, and its activity is post-translationally regulated by O-GlcNAcylation and transcriptionally suppressed under hypoxia via miR-210 [PMID:19841065, PMID:38778315, PMID:20498629]. Loss-of-function mutations in COX10 cause autosomal recessive COX deficiency presenting as Leigh-like syndrome and progressive mitochondrial myopathy, confirmed by complementation rescue in patient fibroblasts and yeast [PMID:10767350, PMID:15455402, PMID:16103131].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Identification of COX10 as a nuclear gene required post-translationally for cytochrome oxidase assembly established that COX biogenesis depends on dedicated nuclear-encoded factors beyond the structural subunits themselves.\",\n      \"evidence\": \"Genetic complementation of respiratory-deficient yeast mutants, nucleotide sequencing, and topological prediction of nine transmembrane segments\",\n      \"pmids\": [\"2167310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic function not yet determined\", \"Subcellular localization to mitochondrial inner membrane not directly demonstrated\", \"Mammalian ortholog not yet identified\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Biochemical analysis of heme constituents in cox10 mutant yeast demonstrated that COX10 catalyzes the farnesylation of protoheme to heme O, resolving its enzymatic identity as a heme A:farnesyltransferase.\",\n      \"evidence\": \"Chromatographic heme analysis in yeast cox10Δ mutants showing absence of heme O and heme A\",\n      \"pmids\": [\"8118433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro reconstitution of farnesyltransferase activity not performed\", \"Substrate specificity (farnesyl-PP vs. other isoprenoids) not directly tested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Functional complementation of yeast cox10Δ by human COX10 cDNA confirmed cross-species conservation of enzymatic function and enabled study of the human enzyme.\",\n      \"evidence\": \"Isolation of human cDNA from expression library by yeast complementation, Southern blot confirmation\",\n      \"pmids\": [\"8078902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human enzyme kinetics not characterized\", \"Tissue expression pattern not mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery of a pathogenic homozygous COX10 missense mutation in a patient with COX deficiency established COX10 as a Mendelian disease gene and linked heme A biosynthesis to human mitochondrial disease.\",\n      \"evidence\": \"Genome-wide linkage analysis, mutation identification, and yeast complementation assay\",\n      \"pmids\": [\"10767350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype spectrum not yet defined\", \"Residual enzymatic activity of mutant protein not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Quantitative measurements in patient tissues and rescue experiments placed COX10 enzymatic activity upstream of COX1-COX4-COX5A subcomplex formation, defining its position in the assembly pathway and showing that heme A content directly determines COX holoenzyme abundance.\",\n      \"evidence\": \"Blue native PAGE of assembly intermediates across COX10-, SCO1-, and SURF1-deficient fibroblasts; retroviral complementation; heme A spectroscopic quantification\",\n      \"pmids\": [\"12928484\", \"14607829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between COX10 and COX1 during heme insertion not demonstrated\", \"Mechanism of heme A transfer to COX1 unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of a start-codon mutation causing Leigh-like disease expanded the clinical spectrum and confirmed by overexpression rescue that even partial loss of COX10 protein is sufficient to cause severe COX deficiency.\",\n      \"evidence\": \"2D gel electrophoresis and COX10 overexpression rescue in patient fibroblasts\",\n      \"pmids\": [\"15455402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold of residual COX10 activity compatible with health not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A skeletal-muscle-specific Cox10 knockout mouse demonstrated in vivo that COX10-dependent heme A synthesis is essential for muscle COX activity and normal contractile function, providing an animal model of mitochondrial myopathy.\",\n      \"evidence\": \"Cre-lox conditional knockout (MLC1f-Cre), COX activity assays, force measurements\",\n      \"pmids\": [\"16103131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether compensatory metabolic remodeling occurs over time not fully characterized\", \"Cardiac-specific consequences not addressed in this model\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic suppressor analysis in yeast revealed that COX10 functions as a homo-oligomeric complex stabilized by the Coa2 assembly factor, and that complex integrity is essential for its catalytic activity in heme A biosynthesis.\",\n      \"evidence\": \"Gain-of-function N196K suppressor of coa2Δ, epistasis with cox15Δ, oligomeric complex size analysis\",\n      \"pmids\": [\"19841065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomeric stoichiometry not determined\", \"Whether Coa2-like stabilization occurs in mammalian cells unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of COX10 mRNA as a direct target of hypoxia-induced miR-210 revealed a transcriptional regulatory axis linking oxygen sensing to mitochondrial electron transport chain remodeling.\",\n      \"evidence\": \"miRNA target identification in cancer cell lines under hypoxia, mitochondrial function and ROS assays\",\n      \"pmids\": [\"20498629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct 3'UTR reporter validation not extensively detailed\", \"Relative contribution of COX10 versus ISCU suppression to the metabolic phenotype not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"NK cell-specific Cox10 deletion demonstrated that Complex IV-dependent oxidative phosphorylation is dispensable for homeostatic NK cell proliferation but specifically required for antigen-driven clonal expansion and memory formation, assigning COX10 a cell-type-specific immunological role.\",\n      \"evidence\": \"Ncr1-Cre conditional KO mice, MCMV infection, flow cytometry, metabolic flux analysis\",\n      \"pmids\": [\"34077722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the metabolic requirement extends to other lymphocyte populations not tested\", \"Mechanism by which glycolytic compensation fails to support clonal expansion unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that O-GlcNAcylation of COX10 protein by OGT enhances mitochondrial function during ischemia-reperfusion established post-translational modification as a regulatory mechanism for COX10 activity in the heart.\",\n      \"evidence\": \"Langendorff heart model, immunoprecipitation for O-GlcNAc, OGT/OGA pharmacological modulation\",\n      \"pmids\": [\"38778315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific O-GlcNAcylation site(s) on COX10 not mapped\", \"Whether O-GlcNAcylation affects COX10 catalytic activity directly or its stability/oligomerization not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Systematic functional phenotyping of 25 human COX10 missense variants in yeast provided a quantitative genotype-activity map, directly correlating variant-specific COX10 residues with enzymatic output.\",\n      \"evidence\": \"Heterologous expression in yeast, COX activity measurement, non-fermentable carbon growth assays\",\n      \"pmids\": [\"39152498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activity measurements performed in yeast, not in human cells\", \"Structure-function mapping limited by absence of an atomic-resolution COX10 structure\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No atomic-resolution structure of COX10 exists, the mechanism of heme O transfer from COX10 to COX1 remains undefined, and the mammalian equivalent of the Coa2-dependent oligomeric regulation has not been established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model at atomic resolution\", \"Heme O handoff mechanism to COX1 unknown\", \"Mammalian COX10 oligomeric state and its regulators uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 3, 4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 4, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 4, 8]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 6, 10]}\n    ],\n    \"complexes\": [\n      \"COX10 homo-oligomeric complex\"\n    ],\n    \"partners\": [\n      \"COA2\",\n      \"COX15\",\n      \"MT-CO1\",\n      \"OGT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}