{"gene":"CMC2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2010,"finding":"Yeast Cmc2 (ortholog of human CMC2) localizes to the mitochondrial inner membrane facing the intermembrane space, and is essential for cytochrome c oxidase biogenesis; in its absence, cytochrome c oxidase activity and cellular respiration are undetectable.","method":"Subcellular fractionation/localization, spectrophotometric and polarographic activity assays in S. cerevisiae cmc2 deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (spectrophotometric COX activity, polarographic respiration, fractionation) in yeast and functional validation extended to human CMC2 and C. elegans knockdown","pmids":["20220131"],"is_preprint":false},{"year":2010,"finding":"Cmc2 physically interacts with Cmc1 (its close homologue); absence of Cmc2 causes a 5-fold increase in Cmc1 accumulation in mitochondrial membranes, and CMC1 overexpression cannot rescue the respiratory defect of cmc2 mutants (and vice versa), indicating cooperative but non-overlapping functions.","method":"Co-immunoprecipitation / physical interaction assay, Western blot quantification, complementation assays in yeast","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic and biochemical evidence (Co-IP, complementation failure, protein level changes) within a single rigorous study","pmids":["20220131"],"is_preprint":false},{"year":2010,"finding":"Cmc2 affects mitochondrial Sod1 (CuZn-superoxide dismutase) activity: cmc2 null cells show 2-fold increased mitochondrial Sod1 activity, while CMC2 overexpression reduces Sod1 activity to ~60% of wild-type, implicating Cmc2 in mitochondrial copper metabolism.","method":"Sod1 enzymatic activity assays in cmc2 deletion and CMC2 overexpression yeast strains","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — enzymatic activity measurements in a single study, single lab, no direct copper-binding assay","pmids":["20220131"],"is_preprint":false},{"year":2010,"finding":"Human CMC2 localizes to mitochondria, and CMC2 expression knockdown in C. elegans produces cytochrome c oxidase deficiency, demonstrating functional conservation from yeast to humans.","method":"Mitochondrial localization (human cells), RNAi knockdown in C. elegans with COX activity readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species validation (human localization + C. elegans KD phenotype) in a single study","pmids":["20220131"],"is_preprint":false}],"current_model":"CMC2 (human) encodes a conserved mitochondrial twin Cx9C intermembrane space protein that localizes to the inner mitochondrial membrane and is required for cytochrome c oxidase biogenesis and cellular respiration; it physically interacts with its paralogue CMC1, modulates mitochondrial copper delivery (affecting both COX and Sod1 activity), and has cooperative but non-overlapping functions with CMC1."},"narrative":{"mechanistic_narrative":"CMC2 encodes a conserved mitochondrial intermembrane-space protein required for cytochrome c oxidase (COX) biogenesis and cellular respiration; in its absence, COX activity and respiration are undetectable [PMID:20220131]. The protein localizes to the inner mitochondrial membrane facing the intermembrane space [PMID:20220131] and physically interacts with its close homologue CMC1, with which it has cooperative but non-overlapping functions: loss of CMC2 causes CMC1 to over-accumulate in mitochondrial membranes, and neither paralogue can rescue the respiratory defect caused by loss of the other [PMID:20220131]. CMC2 also influences mitochondrial copper metabolism, modulating CuZn-superoxide dismutase (Sod1) activity in opposite directions upon deletion versus overexpression [PMID:20220131]. Mitochondrial localization of human CMC2 and the COX-deficiency phenotype upon knockdown in C. elegans establish that this function is conserved from yeast to humans [PMID:20220131]. Beyond these findings from a single foundational study, no further mechanistic detail — including direct copper binding or a structural model — has been characterized in the available corpus.","teleology":[{"year":2010,"claim":"Established that CMC2 is an intermembrane-space inner-membrane protein essential for cytochrome c oxidase assembly, defining its core cellular role in respiration.","evidence":"Subcellular fractionation plus spectrophotometric COX activity and polarographic respiration assays in S. cerevisiae cmc2 deletion mutants","pmids":["20220131"],"confidence":"High","gaps":["The molecular step in COX biogenesis that CMC2 catalyzes or chaperones is not defined","No structural basis for inner-membrane/intermembrane-space topology","No identified COX assembly intermediate dependent on CMC2"]},{"year":2010,"claim":"Showed that CMC2 acts in concert with its paralogue CMC1 through physical interaction yet performs a distinct, non-redundant function, clarifying the genetic architecture of the CMC family.","evidence":"Co-immunoprecipitation, Western-blot quantification of CMC1 accumulation, and reciprocal overexpression/complementation assays in yeast","pmids":["20220131"],"confidence":"High","gaps":["The interaction interface and stoichiometry of the CMC1-CMC2 complex are unknown","Why CMC1 accumulates when CMC2 is lost is mechanistically unexplained","Whether the two proteins act on the same or sequential COX assembly substrates is unresolved"]},{"year":2010,"claim":"Linked CMC2 to mitochondrial copper handling by demonstrating dose-dependent, opposite effects on Sod1 activity, suggesting a role in copper trafficking that connects COX and Sod1 metalation.","evidence":"Sod1 enzymatic activity assays in cmc2 deletion and CMC2 overexpression yeast strains","pmids":["20220131"],"confidence":"Medium","gaps":["No direct copper-binding assay was performed","The mechanism by which CMC2 redistributes copper between COX and Sod1 is not established","Effect on Sod1 may be indirect"]},{"year":2010,"claim":"Demonstrated functional conservation of CMC2 from yeast to metazoans, validating yeast findings as a model for the human protein.","evidence":"Mitochondrial localization of human CMC2 and RNAi knockdown in C. elegans with COX activity readout","pmids":["20220131"],"confidence":"Medium","gaps":["Human CMC2 partners and assembly role not directly tested in human cells","No human disease link established","C. elegans phenotype not extended to respiration measurements"]},{"year":null,"claim":"The direct biochemical activity of CMC2 — whether it binds copper, the COX assembly intermediate it acts upon, and its role in human cells — remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct metal-binding assay","No defined COX assembly substrate or intermediate","No human cell loss-of-function or structural characterization in the corpus"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CMC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRP2","full_name":"COX assembly mitochondrial protein 2 homolog","aliases":[],"length_aa":79,"mass_kda":9.5,"function":"May be involved in cytochrome c oxidase biogenesis","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9NRP2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CMC2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CMC2","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CMC2"},"hgnc":{"alias_symbol":["DC13","MGC45036"],"prev_symbol":["C16orf61"]},"alphafold":{"accession":"Q9NRP2","domains":[{"cath_id":"1.10.287","chopping":"13-72","consensus_level":"high","plddt":95.0715,"start":13,"end":72}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRP2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRP2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRP2-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CMC2","jax_strain_url":"https://www.jax.org/strain/search?query=CMC2"},"sequence":{"accession":"Q9NRP2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRP2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRP2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRP2"}},"corpus_meta":[{"pmid":"23825944","id":"PMC_23825944","title":"DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23825944","citation_count":62,"is_preprint":false},{"pmid":"20220131","id":"PMC_20220131","title":"The conserved mitochondrial twin Cx9C protein Cmc2 Is a Cmc1 homologue essential for cytochrome c oxidase biogenesis.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20220131","citation_count":34,"is_preprint":false},{"pmid":"24086245","id":"PMC_24086245","title":"Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24086245","citation_count":33,"is_preprint":false},{"pmid":"32860098","id":"PMC_32860098","title":"Chemically modified curcumin (CMC2.24) alleviates osteoarthritis progression by restoring cartilage homeostasis and inhibiting chondrocyte apoptosis via the NF-κB/HIF-2α axis.","date":"2020","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/32860098","citation_count":29,"is_preprint":false},{"pmid":"29339517","id":"PMC_29339517","title":"Infected erythrocytes expressing DC13 PfEMP1 differ from recombinant proteins in EPCR-binding function.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29339517","citation_count":22,"is_preprint":false},{"pmid":"29683208","id":"PMC_29683208","title":"A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras.","date":"2018","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/29683208","citation_count":12,"is_preprint":false},{"pmid":"33574457","id":"PMC_33574457","title":"IgG acquisition against PfEMP1 PF11_0521 domain cassette DC13, DBLβ3_D4 domain, and peptides located within these constructs in children with cerebral malaria.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33574457","citation_count":9,"is_preprint":false},{"pmid":"16228371","id":"PMC_16228371","title":"The dc13 gene upstream of ictB is involved in rapid induction of the high affinity Na(+) dependent HCO(3) (-) transporter in cyanobacteria.","date":"2003","source":"Photosynthesis research","url":"https://pubmed.ncbi.nlm.nih.gov/16228371","citation_count":8,"is_preprint":false},{"pmid":"16233338","id":"PMC_16233338","title":"Cloning and transcription analysis of the Aspergillus aculeatus No. F-50 endoglucanase 2 (cmc2) gene.","date":"2002","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/16233338","citation_count":6,"is_preprint":false},{"pmid":"36860795","id":"PMC_36860795","title":"Efficacy of a Novel Pleiotropic MMP-Inhibitor, CMC2.24, in a Long-Term Diabetes Rat Model with Severe Hyperglycemia-Induced Oral Bone Loss.","date":"2023","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/36860795","citation_count":5,"is_preprint":false},{"pmid":"37374155","id":"PMC_37374155","title":"Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation.","date":"2023","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37374155","citation_count":2,"is_preprint":false},{"pmid":"3150519","id":"PMC_3150519","title":"[Study of Pseudomonas aeruginosa DC13 stability during biological purification of industrial sewage from alpha-methyl styrene].","date":"1988","source":"Mikrobiologiia","url":"https://pubmed.ncbi.nlm.nih.gov/3150519","citation_count":1,"is_preprint":false},{"pmid":"41688906","id":"PMC_41688906","title":"Transcriptomics and proteomics insights into carotenoid differentiation in tissue cultured Rehmannia glutinosa root cambial meristematic cells: REG-CMC1 and non-somaclonal REG-CMC2.","date":"2026","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/41688906","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.23.677992","title":"Identification of Novel Fusion Genes in Pediatric B-ALL patients Using Whole Transcriptome Sequencing","date":"2025-09-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.23.677992","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10452,"output_tokens":989,"usd":0.023096,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7507,"output_tokens":1746,"usd":0.040592,"stage2_stop_reason":"end_turn"},"total_usd":0.063688,"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\": 2010,\n      \"finding\": \"Yeast Cmc2 (ortholog of human CMC2) localizes to the mitochondrial inner membrane facing the intermembrane space, and is essential for cytochrome c oxidase biogenesis; in its absence, cytochrome c oxidase activity and cellular respiration are undetectable.\",\n      \"method\": \"Subcellular fractionation/localization, spectrophotometric and polarographic activity assays in S. cerevisiae cmc2 deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (spectrophotometric COX activity, polarographic respiration, fractionation) in yeast and functional validation extended to human CMC2 and C. elegans knockdown\",\n      \"pmids\": [\"20220131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cmc2 physically interacts with Cmc1 (its close homologue); absence of Cmc2 causes a 5-fold increase in Cmc1 accumulation in mitochondrial membranes, and CMC1 overexpression cannot rescue the respiratory defect of cmc2 mutants (and vice versa), indicating cooperative but non-overlapping functions.\",\n      \"method\": \"Co-immunoprecipitation / physical interaction assay, Western blot quantification, complementation assays in yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic and biochemical evidence (Co-IP, complementation failure, protein level changes) within a single rigorous study\",\n      \"pmids\": [\"20220131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cmc2 affects mitochondrial Sod1 (CuZn-superoxide dismutase) activity: cmc2 null cells show 2-fold increased mitochondrial Sod1 activity, while CMC2 overexpression reduces Sod1 activity to ~60% of wild-type, implicating Cmc2 in mitochondrial copper metabolism.\",\n      \"method\": \"Sod1 enzymatic activity assays in cmc2 deletion and CMC2 overexpression yeast strains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — enzymatic activity measurements in a single study, single lab, no direct copper-binding assay\",\n      \"pmids\": [\"20220131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human CMC2 localizes to mitochondria, and CMC2 expression knockdown in C. elegans produces cytochrome c oxidase deficiency, demonstrating functional conservation from yeast to humans.\",\n      \"method\": \"Mitochondrial localization (human cells), RNAi knockdown in C. elegans with COX activity readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species validation (human localization + C. elegans KD phenotype) in a single study\",\n      \"pmids\": [\"20220131\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CMC2 (human) encodes a conserved mitochondrial twin Cx9C intermembrane space protein that localizes to the inner mitochondrial membrane and is required for cytochrome c oxidase biogenesis and cellular respiration; it physically interacts with its paralogue CMC1, modulates mitochondrial copper delivery (affecting both COX and Sod1 activity), and has cooperative but non-overlapping functions with CMC1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CMC2 encodes a conserved mitochondrial intermembrane-space protein required for cytochrome c oxidase (COX) biogenesis and cellular respiration; in its absence, COX activity and respiration are undetectable [#0]. The protein localizes to the inner mitochondrial membrane facing the intermembrane space [#0] and physically interacts with its close homologue CMC1, with which it has cooperative but non-overlapping functions: loss of CMC2 causes CMC1 to over-accumulate in mitochondrial membranes, and neither paralogue can rescue the respiratory defect caused by loss of the other [#1]. CMC2 also influences mitochondrial copper metabolism, modulating CuZn-superoxide dismutase (Sod1) activity in opposite directions upon deletion versus overexpression [#2]. Mitochondrial localization of human CMC2 and the COX-deficiency phenotype upon knockdown in C. elegans establish that this function is conserved from yeast to humans [#3]. Beyond these findings from a single foundational study, no further mechanistic detail — including direct copper binding or a structural model — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that CMC2 is an intermembrane-space inner-membrane protein essential for cytochrome c oxidase assembly, defining its core cellular role in respiration.\",\n      \"evidence\": \"Subcellular fractionation plus spectrophotometric COX activity and polarographic respiration assays in S. cerevisiae cmc2 deletion mutants\",\n      \"pmids\": [\"20220131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular step in COX biogenesis that CMC2 catalyzes or chaperones is not defined\", \"No structural basis for inner-membrane/intermembrane-space topology\", \"No identified COX assembly intermediate dependent on CMC2\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that CMC2 acts in concert with its paralogue CMC1 through physical interaction yet performs a distinct, non-redundant function, clarifying the genetic architecture of the CMC family.\",\n      \"evidence\": \"Co-immunoprecipitation, Western-blot quantification of CMC1 accumulation, and reciprocal overexpression/complementation assays in yeast\",\n      \"pmids\": [\"20220131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The interaction interface and stoichiometry of the CMC1-CMC2 complex are unknown\", \"Why CMC1 accumulates when CMC2 is lost is mechanistically unexplained\", \"Whether the two proteins act on the same or sequential COX assembly substrates is unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked CMC2 to mitochondrial copper handling by demonstrating dose-dependent, opposite effects on Sod1 activity, suggesting a role in copper trafficking that connects COX and Sod1 metalation.\",\n      \"evidence\": \"Sod1 enzymatic activity assays in cmc2 deletion and CMC2 overexpression yeast strains\",\n      \"pmids\": [\"20220131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct copper-binding assay was performed\", \"The mechanism by which CMC2 redistributes copper between COX and Sod1 is not established\", \"Effect on Sod1 may be indirect\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated functional conservation of CMC2 from yeast to metazoans, validating yeast findings as a model for the human protein.\",\n      \"evidence\": \"Mitochondrial localization of human CMC2 and RNAi knockdown in C. elegans with COX activity readout\",\n      \"pmids\": [\"20220131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human CMC2 partners and assembly role not directly tested in human cells\", \"No human disease link established\", \"C. elegans phenotype not extended to respiration measurements\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical activity of CMC2 — whether it binds copper, the COX assembly intermediate it acts upon, and its role in human cells — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct metal-binding assay\", \"No defined COX assembly substrate or intermediate\", \"No human cell loss-of-function or structural characterization in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CMC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}