{"gene":"COX6C","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2000,"finding":"A chromosomal rearrangement in uterine leiomyoma creates a fusion transcript in which the first 3 exons of HMGIC (encoding its 3 DNA-binding domains) are fused to exon 2 of COX6C, placing COX6C as the fusion partner of HMGIC at the 12q15/8q22-23 translocation breakpoint.","method":"3' RACE, fusion cDNA cloning, nucleotide sequence analysis","journal":"Genes, Chromosomes & Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning and sequencing of fusion cDNA from patient tissue, single lab, single method","pmids":["10679920"],"is_preprint":false},{"year":2018,"finding":"DAZAP1, an RNA-binding protein, binds cox6c mRNA in an intron-dependent manner (the last intron is sufficient for loading) and acts as a negative regulator of cox6c pre-mRNA splicing, reducing mature COX6C protein levels; both DAZAP1 knockdown and COX6C overexpression retard cell growth.","method":"RNA-binding assays with genomic vs. intronless expression vectors, DAZAP1 overexpression/knockdown, RT-PCR for pre-mRNA accumulation, western blot for COX6C protein, cell growth assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab (binding assay, KD/OE, protein quantification, growth assay) but not independently replicated","pmids":["29505834"],"is_preprint":false},{"year":2024,"finding":"COX6C knockdown impairs mitochondrial fusion and oxidative phosphorylation, leading to ROS accumulation and AMPK pathway activation, which disrupts spindle formation and chromosome segregation, activates the spindle assembly checkpoint, causes mitotic arrest (S-G2/M), and induces apoptosis in lung adenocarcinoma cells.","method":"siRNA knockdown, cell cycle analysis (flow cytometry), mitochondrial fusion/morphology assays, ROS measurement, AMPK pathway western blot, spindle formation microscopy, apoptosis assay","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in single lab establishing a mechanistic pathway from COX6C depletion to mitotic arrest via ROS-AMPK","pmids":["38242874"],"is_preprint":false},{"year":2024,"finding":"siRNA-mediated knockdown of COX6C reduces intracellular ATP levels and mitochondrial membrane potential, causes mitochondrial structural abnormalities (shortening, swelling, incomplete cristae), and inhibits proliferation of multiple myeloma cells, indicating COX6C supports MM cell growth by maintaining mitochondrial integrity and ATP production.","method":"siRNA knockdown, MTT proliferation assay, flow cytometry for mitochondrial membrane potential and ATP levels, transmission electron microscopy","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts (ATP, ΔΨm, TEM morphology, proliferation) in single lab","pmids":["41502258"],"is_preprint":false},{"year":2024,"finding":"In a myocardial infarction model, COX6C expression is elevated; si-COX6C transfection blocks the ability of methylprotodioscin (MPD) to reduce NF-κB-mediated inflammation and oxidative stress, placing COX6C downstream of MPD's cardioprotective mechanism.","method":"TMT-based proteomics, siRNA knockdown of COX6C in hypoxia-injured cardiomyocytes, western blot for NF-κB/Nrf2/SOD, ROS measurement, mouse MI model","journal":"Biomedicine & Pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA rescue experiment establishes pathway position but proteomics-driven discovery without mechanistic reconstitution","pmids":["39321507"],"is_preprint":false},{"year":2026,"finding":"NHE7 (SLC9A7) promotes EC progression by upregulating COX6C expression, which enhances oxidative phosphorylation and drives endoplasmic reticulum stress; hypoxia-induced histone lactylation transcriptionally activates NHE7, placing COX6C downstream of the NHE7-OXPHOS-ER stress axis.","method":"Overexpression/knockdown functional assays, xenograft model, ChIP for histone lactylation, pharmacological inhibitors (4-PBA, 2-DG, sodium oxamate), western blot, transcriptomic analysis","journal":"Apoptosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, COX6C placed in pathway by correlative western blot evidence within a broader NHE7 study, no direct reconstitution of COX6C's mechanism","pmids":["41575611"],"is_preprint":false}],"current_model":"COX6C encodes a nuclear-genome-encoded subunit of mitochondrial Complex IV (cytochrome c oxidase) that is essential for oxidative phosphorylation and ATP production; its expression is post-transcriptionally suppressed by the RNA-binding protein DAZAP1 via intron-dependent loading that reduces pre-mRNA splicing efficiency, and loss of COX6C triggers ROS accumulation, AMPK activation, spindle assembly checkpoint engagement, and apoptosis, while in cancer contexts its copy-number amplification or transcriptional upregulation sustains mitochondrial function and cell proliferation."},"narrative":{"mechanistic_narrative":"COX6C encodes a subunit of mitochondrial Complex IV whose depletion impairs oxidative phosphorylation, lowers ATP and mitochondrial membrane potential, and produces structural mitochondrial defects, thereby constraining cell proliferation [PMID:41502258]. Loss of COX6C further impairs mitochondrial fusion and drives ROS accumulation and AMPK pathway activation, which disrupts spindle formation and chromosome segregation, engages the spindle assembly checkpoint, and ultimately causes mitotic arrest and apoptosis in lung adenocarcinoma cells [PMID:38242874]. COX6C protein levels are post-transcriptionally restrained by the RNA-binding protein DAZAP1, which loads onto cox6c pre-mRNA in an intron-dependent manner and negatively regulates its splicing; both DAZAP1 knockdown and COX6C overexpression retard cell growth [PMID:29505834]. COX6C was also identified as the fusion partner of HMGIC at a 12q15/8q22-23 translocation breakpoint in uterine leiomyoma [PMID:10679920]. Beyond these findings, the structural basis of COX6C incorporation into Complex IV has not been characterized in the available corpus.","teleology":[{"year":2000,"claim":"Establishing COX6C as a recurrent rearrangement partner located the gene at a defined chromosomal breakpoint and linked it to a benign tumor through gene fusion rather than through its enzymatic role.","evidence":"3' RACE and fusion cDNA cloning/sequencing from uterine leiomyoma tissue identifying an HMGIC-COX6C fusion transcript","pmids":["10679920"],"confidence":"Medium","gaps":["Does not establish whether the fusion alters COX6C function or expression","No functional consequence of the fusion protein tested"]},{"year":2018,"claim":"Identifying DAZAP1 as a negative regulator answered how COX6C protein output is controlled post-transcriptionally, revealing intron-dependent splicing suppression as a tuning mechanism with growth consequences.","evidence":"RNA-binding assays comparing genomic vs intronless vectors, DAZAP1 knockdown/overexpression, RT-PCR for pre-mRNA accumulation, and cell growth assays","pmids":["29505834"],"confidence":"Medium","gaps":["Mechanism by which intron loading impedes splicing not resolved","Not independently replicated","Physiological contexts where DAZAP1 regulates COX6C unknown"]},{"year":2024,"claim":"Functional depletion studies connected COX6C loss to a defined cascade from mitochondrial dysfunction to mitotic arrest, establishing it as a determinant of cell viability beyond simple bioenergetics.","evidence":"siRNA knockdown in lung adenocarcinoma cells with ROS, AMPK western blot, mitochondrial fusion/morphology, spindle microscopy, cell cycle and apoptosis assays; and siRNA knockdown in multiple myeloma cells with ATP, membrane potential, TEM and proliferation readouts","pmids":["38242874","41502258"],"confidence":"Medium","gaps":["Causal ordering of ROS-AMPK-spindle steps relies on correlative pathway readouts","Direct demonstration of Complex IV activity loss not provided","Single-lab findings per cancer type"]},{"year":2024,"claim":"Proteomic and pathway-positioning studies placed COX6C downstream of regulatory signals in disease contexts, framing it as an effector of OXPHOS-dependent phenotypes.","evidence":"siRNA rescue in cardiomyocyte/MI model placing COX6C downstream of methylprotodioscin; and overexpression/knockdown plus xenograft and ChIP placing COX6C downstream of an NHE7-OXPHOS-ER stress axis","pmids":["39321507","41575611"],"confidence":"Low","gaps":["COX6C placement is correlative western-blot/proteomics evidence without reconstitution of its mechanism","Direct molecular link between upstream regulators and COX6C activity not demonstrated"]},{"year":null,"claim":"How COX6C assembles into and modulates Complex IV at the structural and biochemical level remains unresolved in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of COX6C within Complex IV","No direct measurement of holoenzyme activity attributable to COX6C","Regulatory inputs beyond DAZAP1 uncharacterized"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3]}],"complexes":["cytochrome c oxidase (Complex IV)"],"partners":["DAZAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09669","full_name":"Cytochrome c oxidase subunit 6C","aliases":["Cytochrome c oxidase polypeptide VIc"],"length_aa":75,"mass_kda":8.8,"function":"Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P09669/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/COX6C","classification":"Common Essential","n_dependent_lines":624,"n_total_lines":1208,"dependency_fraction":0.5165562913907285},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RAC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COX6C","total_profiled":1310},"omim":[{"mim_id":"618064","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR 16; COX16","url":"https://www.omim.org/entry/618064"},{"mim_id":"617465","title":"SMALL INTEGRAL MEMBRANE PROTEIN 20; SMIM20","url":"https://www.omim.org/entry/617465"},{"mim_id":"616274","title":"MICRO RNA 4276; MIR4276","url":"https://www.omim.org/entry/616274"},{"mim_id":"603774","title":"CYTOCHROME c OXIDASE, SUBUNIT 7C; COX7C","url":"https://www.omim.org/entry/603774"},{"mim_id":"603773","title":"CYTOCHROME c OXIDASE, SUBUNIT 5A; COX5A","url":"https://www.omim.org/entry/603773"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COX6C"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P09669","domains":[{"cath_id":"4.10.93.10","chopping":"15-67","consensus_level":"high","plddt":97.4475,"start":15,"end":67}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09669","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09669-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09669-F1-predicted_aligned_error_v6.png","plddt_mean":94.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COX6C","jax_strain_url":"https://www.jax.org/strain/search?query=COX6C"},"sequence":{"accession":"P09669","fasta_url":"https://rest.uniprot.org/uniprotkb/P09669.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09669/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09669"}},"corpus_meta":[{"pmid":"10679920","id":"PMC_10679920","title":"Novel gene fusion of COX6C at 8q22-23 to HMGIC at 12q15 in a uterine leiomyoma.","date":"2000","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10679920","citation_count":32,"is_preprint":false},{"pmid":"33527004","id":"PMC_33527004","title":"Differential expression and clinical significance of COX6C in human diseases.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/33527004","citation_count":31,"is_preprint":false},{"pmid":"35879322","id":"PMC_35879322","title":"Novel role of COX6c in the regulation of oxidative phosphorylation and diseases.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35879322","citation_count":31,"is_preprint":false},{"pmid":"29505834","id":"PMC_29505834","title":"Specific intron-dependent loading of DAZAP1 onto the cox6c transcript suppresses pre-mRNA splicing efficacy and induces cell growth retardation.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29505834","citation_count":13,"is_preprint":false},{"pmid":"38242874","id":"PMC_38242874","title":"COX6C expression driven by copy amplification of 8q22.2 regulates cell proliferation via mediation of mitosis by ROS-AMPK signaling in lung adenocarcinoma.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38242874","citation_count":11,"is_preprint":false},{"pmid":"39321507","id":"PMC_39321507","title":"TMT-based proteomics reveals methylprotodioscin alleviates oxidative stress and inflammation via COX6C in myocardial infraction.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/39321507","citation_count":3,"is_preprint":false},{"pmid":"26442366","id":"PMC_26442366","title":"[Relation between Injury Time and the Expression of COX6C mRNA in Skeletal Muscle of Rats after Contusion].","date":"2015","source":"Fa yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/26442366","citation_count":3,"is_preprint":false},{"pmid":"39655053","id":"PMC_39655053","title":"Role of COX6C and NDUFB3 in septic shock and stroke.","date":"2024","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/39655053","citation_count":2,"is_preprint":false},{"pmid":"41575611","id":"PMC_41575611","title":"Hypoxic glycolysis-driven histone lactylation activates NHE7 to promote endometrial cancer progression via COX6C-mediated endoplasmic reticulum stress.","date":"2026","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/41575611","citation_count":0,"is_preprint":false},{"pmid":"41502258","id":"PMC_41502258","title":"[COX6C Promotes the Proliferation of Multiple Myeloma Cells by Increasing Intracellular ATP Levels].","date":"2025","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/41502258","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6787,"output_tokens":1625,"usd":0.022368,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8479,"output_tokens":1892,"usd":0.044847,"stage2_stop_reason":"end_turn"},"total_usd":0.067215,"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\": 2000,\n      \"finding\": \"A chromosomal rearrangement in uterine leiomyoma creates a fusion transcript in which the first 3 exons of HMGIC (encoding its 3 DNA-binding domains) are fused to exon 2 of COX6C, placing COX6C as the fusion partner of HMGIC at the 12q15/8q22-23 translocation breakpoint.\",\n      \"method\": \"3' RACE, fusion cDNA cloning, nucleotide sequence analysis\",\n      \"journal\": \"Genes, Chromosomes & Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning and sequencing of fusion cDNA from patient tissue, single lab, single method\",\n      \"pmids\": [\"10679920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DAZAP1, an RNA-binding protein, binds cox6c mRNA in an intron-dependent manner (the last intron is sufficient for loading) and acts as a negative regulator of cox6c pre-mRNA splicing, reducing mature COX6C protein levels; both DAZAP1 knockdown and COX6C overexpression retard cell growth.\",\n      \"method\": \"RNA-binding assays with genomic vs. intronless expression vectors, DAZAP1 overexpression/knockdown, RT-PCR for pre-mRNA accumulation, western blot for COX6C protein, cell growth assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab (binding assay, KD/OE, protein quantification, growth assay) but not independently replicated\",\n      \"pmids\": [\"29505834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COX6C knockdown impairs mitochondrial fusion and oxidative phosphorylation, leading to ROS accumulation and AMPK pathway activation, which disrupts spindle formation and chromosome segregation, activates the spindle assembly checkpoint, causes mitotic arrest (S-G2/M), and induces apoptosis in lung adenocarcinoma cells.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis (flow cytometry), mitochondrial fusion/morphology assays, ROS measurement, AMPK pathway western blot, spindle formation microscopy, apoptosis assay\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in single lab establishing a mechanistic pathway from COX6C depletion to mitotic arrest via ROS-AMPK\",\n      \"pmids\": [\"38242874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"siRNA-mediated knockdown of COX6C reduces intracellular ATP levels and mitochondrial membrane potential, causes mitochondrial structural abnormalities (shortening, swelling, incomplete cristae), and inhibits proliferation of multiple myeloma cells, indicating COX6C supports MM cell growth by maintaining mitochondrial integrity and ATP production.\",\n      \"method\": \"siRNA knockdown, MTT proliferation assay, flow cytometry for mitochondrial membrane potential and ATP levels, transmission electron microscopy\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts (ATP, ΔΨm, TEM morphology, proliferation) in single lab\",\n      \"pmids\": [\"41502258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a myocardial infarction model, COX6C expression is elevated; si-COX6C transfection blocks the ability of methylprotodioscin (MPD) to reduce NF-κB-mediated inflammation and oxidative stress, placing COX6C downstream of MPD's cardioprotective mechanism.\",\n      \"method\": \"TMT-based proteomics, siRNA knockdown of COX6C in hypoxia-injured cardiomyocytes, western blot for NF-κB/Nrf2/SOD, ROS measurement, mouse MI model\",\n      \"journal\": \"Biomedicine & Pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA rescue experiment establishes pathway position but proteomics-driven discovery without mechanistic reconstitution\",\n      \"pmids\": [\"39321507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NHE7 (SLC9A7) promotes EC progression by upregulating COX6C expression, which enhances oxidative phosphorylation and drives endoplasmic reticulum stress; hypoxia-induced histone lactylation transcriptionally activates NHE7, placing COX6C downstream of the NHE7-OXPHOS-ER stress axis.\",\n      \"method\": \"Overexpression/knockdown functional assays, xenograft model, ChIP for histone lactylation, pharmacological inhibitors (4-PBA, 2-DG, sodium oxamate), western blot, transcriptomic analysis\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, COX6C placed in pathway by correlative western blot evidence within a broader NHE7 study, no direct reconstitution of COX6C's mechanism\",\n      \"pmids\": [\"41575611\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COX6C encodes a nuclear-genome-encoded subunit of mitochondrial Complex IV (cytochrome c oxidase) that is essential for oxidative phosphorylation and ATP production; its expression is post-transcriptionally suppressed by the RNA-binding protein DAZAP1 via intron-dependent loading that reduces pre-mRNA splicing efficiency, and loss of COX6C triggers ROS accumulation, AMPK activation, spindle assembly checkpoint engagement, and apoptosis, while in cancer contexts its copy-number amplification or transcriptional upregulation sustains mitochondrial function and cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COX6C encodes a subunit of mitochondrial Complex IV whose depletion impairs oxidative phosphorylation, lowers ATP and mitochondrial membrane potential, and produces structural mitochondrial defects, thereby constraining cell proliferation [#3]. Loss of COX6C further impairs mitochondrial fusion and drives ROS accumulation and AMPK pathway activation, which disrupts spindle formation and chromosome segregation, engages the spindle assembly checkpoint, and ultimately causes mitotic arrest and apoptosis in lung adenocarcinoma cells [#2]. COX6C protein levels are post-transcriptionally restrained by the RNA-binding protein DAZAP1, which loads onto cox6c pre-mRNA in an intron-dependent manner and negatively regulates its splicing; both DAZAP1 knockdown and COX6C overexpression retard cell growth [#1]. COX6C was also identified as the fusion partner of HMGIC at a 12q15/8q22-23 translocation breakpoint in uterine leiomyoma [#0]. Beyond these findings, the structural basis of COX6C incorporation into Complex IV has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing COX6C as a recurrent rearrangement partner located the gene at a defined chromosomal breakpoint and linked it to a benign tumor through gene fusion rather than through its enzymatic role.\",\n      \"evidence\": \"3' RACE and fusion cDNA cloning/sequencing from uterine leiomyoma tissue identifying an HMGIC-COX6C fusion transcript\",\n      \"pmids\": [\"10679920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether the fusion alters COX6C function or expression\", \"No functional consequence of the fusion protein tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying DAZAP1 as a negative regulator answered how COX6C protein output is controlled post-transcriptionally, revealing intron-dependent splicing suppression as a tuning mechanism with growth consequences.\",\n      \"evidence\": \"RNA-binding assays comparing genomic vs intronless vectors, DAZAP1 knockdown/overexpression, RT-PCR for pre-mRNA accumulation, and cell growth assays\",\n      \"pmids\": [\"29505834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which intron loading impedes splicing not resolved\", \"Not independently replicated\", \"Physiological contexts where DAZAP1 regulates COX6C unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Functional depletion studies connected COX6C loss to a defined cascade from mitochondrial dysfunction to mitotic arrest, establishing it as a determinant of cell viability beyond simple bioenergetics.\",\n      \"evidence\": \"siRNA knockdown in lung adenocarcinoma cells with ROS, AMPK western blot, mitochondrial fusion/morphology, spindle microscopy, cell cycle and apoptosis assays; and siRNA knockdown in multiple myeloma cells with ATP, membrane potential, TEM and proliferation readouts\",\n      \"pmids\": [\"38242874\", \"41502258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal ordering of ROS-AMPK-spindle steps relies on correlative pathway readouts\", \"Direct demonstration of Complex IV activity loss not provided\", \"Single-lab findings per cancer type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proteomic and pathway-positioning studies placed COX6C downstream of regulatory signals in disease contexts, framing it as an effector of OXPHOS-dependent phenotypes.\",\n      \"evidence\": \"siRNA rescue in cardiomyocyte/MI model placing COX6C downstream of methylprotodioscin; and overexpression/knockdown plus xenograft and ChIP placing COX6C downstream of an NHE7-OXPHOS-ER stress axis\",\n      \"pmids\": [\"39321507\", \"41575611\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"COX6C placement is correlative western-blot/proteomics evidence without reconstitution of its mechanism\", \"Direct molecular link between upstream regulators and COX6C activity not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COX6C assembles into and modulates Complex IV at the structural and biochemical level remains unresolved in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of COX6C within Complex IV\", \"No direct measurement of holoenzyme activity attributable to COX6C\", \"Regulatory inputs beyond DAZAP1 uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"cytochrome c oxidase (Complex IV)\"],\n    \"partners\": [\"DAZAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}