{"gene":"COX7A2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2021,"finding":"SILAC-based complexome profiling of SCAFI-knockout (SCAFIKO) HEK293T cells demonstrated that the majority (~70%) of human respirasomes contain COX7A2 (rather than COX7A2L/SCAFI) bridging Complex IV into the supercomplex, and these COX7A2-containing respirasomes persisted at roughly the same levels when SCAFI was knocked out, establishing COX7A2 as the predominant structural component linking Complex IV into respirasomes.","method":"SILAC-based complexome profiling, CRISPR-Cas9 knockout of SCAFI, native gel electrophoresis","journal":"Biochimica et biophysica acta. Bioenergetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SILAC complexome profiling with genetic knockout (CRISPR-Cas9), quantitative mass spectrometry, multiple orthogonal methods in a single rigorous study","pmids":["33727070"],"is_preprint":false},{"year":2006,"finding":"Overexpression of Cox7a2 in TM3 mouse Leydig cells inhibited LH-induced testosterone secretion and suppressed StAR protein expression, while simultaneously increasing reactive oxygen species (ROS) activity, establishing that Cox7a2 modulates steroidogenesis at least in part through ROS-mediated suppression of StAR.","method":"Transient transfection overexpression, ELISA (testosterone), Western blot (StAR), fluorometric ROS assay","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal methods (ELISA, Western blot, ROS assay) in a single lab study with overexpression model","pmids":["16752004"],"is_preprint":false},{"year":2011,"finding":"Overexpression of Cox7a2 in TM3 mouse Leydig cells decreased phosphorylation of P70S6K and reduced StAR protein expression, thereby inhibiting LH-induced testosterone biosynthesis, implicating autophagy regulatory signaling (via P70S6K) as the mechanism downstream of Cox7a2.","method":"Transfection overexpression, ELISA (testosterone), Western blot (StAR, phospho-P70S6K)","journal":"Zhonghua nan ke xue = National journal of andrology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression model, limited orthogonal validation, published in lower-tier journal","pmids":["21548202"],"is_preprint":false},{"year":2012,"finding":"Fluorescent protein tagging and live-cell imaging showed that Cox7a2 localizes to mitochondria in TM3 Leydig cells, but co-expression of active Ras relocalized Cox7a2 away from mitochondria; expression of dominant-negative Ras restored mitochondrial localization, establishing that Ras signaling regulates the subcellular localization of Cox7a2.","method":"Fluorescent protein fusion (EYFP) live-cell imaging, dominant-negative Ras transfection","journal":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single imaging method, no biochemical validation of the localization change or its functional consequence","pmids":["22898835"],"is_preprint":false},{"year":2021,"finding":"Genome-wide shRNA screen followed by siRNA validation identified Cox7a2 as a gene whose loss-of-function selectively induces apoptosis in HIV-infected macrophages but not in uninfected bystander macrophages; mechanistic follow-up indicated this selective killing involves enhanced ROS production through targeting of respiratory chain Complexes II and IV.","method":"Pooled shRNA genome-wide screen, siRNA knockdown validation, Annexin-V flow cytometry apoptosis assay","journal":"BMC infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased genome-wide screen with orthogonal siRNA validation and functional readout (apoptosis by flow cytometry), single lab","pmids":["34233649"],"is_preprint":false},{"year":1992,"finding":"Northern blot and chromosome mapping of human-rodent cell hybrids established that COX7A2 (COXVIIa-L) encodes the ubiquitously expressed liver-type isoform of cytochrome c oxidase subunit VIIa, present in both muscle and non-muscle tissues, mapping to two loci on chromosomes 4 and 14.","method":"Northern blot, Southern blot hybridization of human-rodent somatic cell hybrids, cDNA cloning","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization with Northern and Southern blots, chromosome mapping, replicated across species","pmids":["1327965"],"is_preprint":false},{"year":1996,"finding":"Promoter deletion analysis demonstrated that a 92-bp region flanking the 5′-end of the COX7AL gene drives most transcriptional activity and contains functional binding sites for NRF-1 and NRF-2 (nuclear respiratory factors) as well as Sp1 motifs; both NRF-1 and NRF-2 sites were shown to be functional, and interaction between the NRF-1 site and an upstream element contributes to expression.","method":"Promoter deletion/reporter assay, electrophoretic mobility shift assay (EMSA) for NRF-1 and NRF-2 binding","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter dissection with reporter assays and binding-site validation, single lab with multiple methods","pmids":["8567667"],"is_preprint":false},{"year":2023,"finding":"Conditional deletion of transcription factor E4F1 in mouse germ cells caused loss of the undifferentiated spermatogonial pool; ChIP/chromatin accessibility analysis showed E4F1 binds the promoter of Cox7a2 (among other respiratory chain genes), establishing E4F1 as a direct transcriptional regulator of Cox7a2 expression in spermatogonia.","method":"Conditional knockout mouse, single-cell RNA-seq, chromatin accessibility (ATAC-seq), ChIP-seq/promoter binding analysis","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined phenotype, chromatin binding data showing direct promoter occupancy, single lab","pmids":["37749649"],"is_preprint":false}],"current_model":"COX7A2 (COXVIIa-L) is the ubiquitously expressed liver-type isoform of cytochrome c oxidase subunit VIIa whose promoter is driven by NRF-1, NRF-2, and Sp1 transcription factors (and directly by E4F1 in spermatogonia); it localizes to mitochondria and, as demonstrated by SILAC complexome profiling, predominantly bridges Complex IV into human respirasomes rather than into the minor SC III₂+IV supercomplex; in Leydig cells its overexpression suppresses LH-induced testosterone production by reducing StAR protein levels via ROS elevation and decreased P70S6K phosphorylation, and its loss-of-function selectively induces apoptosis in HIV-infected macrophages through enhanced ROS production at the respiratory chain."},"narrative":{"mechanistic_narrative":"COX7A2 (COXVIIa-L) is the ubiquitously expressed liver-type isoform of cytochrome c oxidase subunit VIIa, present across muscle and non-muscle tissues [PMID:1327965], and functions as the predominant structural component bridging Complex IV into respiratory chain supercomplexes: SILAC complexome profiling established that the majority of human respirasomes incorporate COX7A2 rather than COX7A2L/SCAFI, and these COX7A2-containing assemblies persist independently of SCAFI [PMID:33727070]. Transcription of COX7A2 is governed by the mitochondrial biogenesis regulators NRF-1 and NRF-2 together with Sp1 acting on a compact proximal promoter [PMID:8567667], and in spermatogonia it is a direct target of E4F1, whose loss depletes the undifferentiated spermatogonial pool [PMID:37749649]. Beyond its core role in oxidative phosphorylation, modulation of COX7A2 levels alters reactive oxygen species output at the respiratory chain: its overexpression in Leydig cells suppresses LH-induced testosterone synthesis by lowering StAR protein through ROS elevation [PMID:16752004], while its loss-of-function selectively triggers apoptosis in HIV-infected macrophages via enhanced ROS production at Complexes II and IV [PMID:34233649].","teleology":[{"year":1992,"claim":"Established the identity and tissue distribution of COX7A2 as a distinct cytochrome c oxidase subunit VIIa isoform, defining the gene whose mechanism would later be dissected.","evidence":"cDNA cloning, Northern/Southern blot, and chromosome mapping in human-rodent cell hybrids","pmids":["1327965"],"confidence":"Medium","gaps":["Did not address how the isoform integrates into the holoenzyme or supercomplexes","Multiple mapped loci left genomic organization ambiguous"]},{"year":1996,"claim":"Resolved how COX7A2 expression is controlled, linking the gene to the nuclear respiratory factor program that coordinates mitochondrial biogenesis.","evidence":"Promoter deletion/reporter assays and EMSA showing functional NRF-1, NRF-2, and Sp1 sites in a 92-bp proximal promoter","pmids":["8567667"],"confidence":"Medium","gaps":["Did not test the promoter in tissue-specific contexts","Functional consequence of NRF binding on respiratory capacity not measured"]},{"year":2006,"claim":"Connected COX7A2 levels to steroidogenic output, showing the subunit can act as a ROS-dependent suppressor of testosterone biosynthesis.","evidence":"Overexpression in TM3 Leydig cells with testosterone ELISA, StAR Western blot, and fluorometric ROS assay","pmids":["16752004"],"confidence":"Medium","gaps":["Overexpression model only; loss-of-function effect on steroidogenesis untested","Causal chain from ROS to StAR suppression not directly demonstrated"]},{"year":2011,"claim":"Extended the steroidogenic mechanism by placing P70S6K signaling downstream of COX7A2 in the suppression of StAR.","evidence":"Overexpression in TM3 Leydig cells with phospho-P70S6K and StAR Western blots and testosterone ELISA","pmids":["21548202"],"confidence":"Low","gaps":["Single overexpression model with limited orthogonal validation in a lower-tier journal","Direct link between P70S6K phosphorylation and StAR levels not established"]},{"year":2012,"claim":"Probed whether COX7A2 subcellular localization is dynamically regulated, implicating Ras signaling in directing it away from mitochondria.","evidence":"EYFP fusion live-cell imaging with active and dominant-negative Ras in TM3 Leydig cells","pmids":["22898835"],"confidence":"Low","gaps":["Single imaging method with no biochemical confirmation of relocalization","Functional consequence of the localization change not tested"]},{"year":2021,"claim":"Defined the core structural role of COX7A2 in respiratory chain organization, showing it, not SCAFI, is the predominant bridge of Complex IV into respirasomes.","evidence":"SILAC complexome profiling with CRISPR-Cas9 SCAFI knockout and native gel electrophoresis in HEK293T cells","pmids":["33727070"],"confidence":"High","gaps":["Structural basis of the COX7A2-respirasome interface not resolved","Physiological consequence of COX7A2 loss on supercomplex assembly not tested"]},{"year":2021,"claim":"Revealed a context-dependent vulnerability whereby loss of COX7A2 selectively kills HIV-infected cells through respiratory-chain ROS.","evidence":"Genome-wide shRNA screen with siRNA validation and Annexin-V flow cytometry in HIV-infected macrophages","pmids":["34233649"],"confidence":"Medium","gaps":["Mechanism linking COX7A2 loss to Complex II/IV ROS not biochemically dissected","Why selectivity is restricted to infected cells unexplained"]},{"year":2023,"claim":"Identified a tissue-specific transcriptional regulator, placing COX7A2 within an E4F1-driven respiratory gene program required for spermatogonial maintenance.","evidence":"Conditional E4F1 knockout mouse with scRNA-seq, ATAC-seq, and ChIP-seq promoter occupancy analysis","pmids":["37749649"],"confidence":"Medium","gaps":["Did not isolate COX7A2's individual contribution to the spermatogonial phenotype","Direct functional rescue by COX7A2 not performed"]},{"year":null,"claim":"How COX7A2's role in respirasome bridging mechanistically connects to its ROS-modulating effects on steroidogenesis and infected-cell apoptosis remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of COX7A2 within the respirasome","Unclear whether ROS phenotypes stem from altered supercomplex assembly","No loss-of-function study of COX7A2 in steroidogenic tissue"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3]}],"pathway":[],"complexes":["respirasome (respiratory chain supercomplex)","cytochrome c oxidase (Complex IV)"],"partners":["COX7A2L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14406","full_name":"Cytochrome c oxidase subunit 7A2, mitochondrial","aliases":["Cytochrome c oxidase subunit VIIa-liver/heart","Cytochrome c oxidase subunit VIIa-L","Cytochrome c oxidase subunit VIIaL"],"length_aa":83,"mass_kda":9.4,"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/P14406/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COX7A2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":383,"dependency_fraction":0.013054830287206266},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MTMR2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COX7A2","total_profiled":1310},"omim":[{"mim_id":"614770","title":"PET100 CYTOCHROME c OXIDASE CHAPERONE; PET100","url":"https://www.omim.org/entry/614770"},{"mim_id":"605771","title":"COX7A2-LIKE PROTEIN; COX7A2L","url":"https://www.omim.org/entry/605771"},{"mim_id":"123997","title":"CYTOCHROME c OXIDASE, SUBUNIT 7A2, PSEUDOGENE 2; COX7A2P2","url":"https://www.omim.org/entry/123997"},{"mim_id":"123996","title":"CYTOCHROME c OXIDASE, SUBUNIT 7A2; COX7A2","url":"https://www.omim.org/entry/123996"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COX7A2"},"hgnc":{"alias_symbol":["COXVIIa-L","COX7AL"],"prev_symbol":[]},"alphafold":{"accession":"P14406","domains":[{"cath_id":"4.10.91.10","chopping":"40-79","consensus_level":"medium","plddt":97.0557,"start":40,"end":79}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14406","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14406-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14406-F1-predicted_aligned_error_v6.png","plddt_mean":88.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COX7A2","jax_strain_url":"https://www.jax.org/strain/search?query=COX7A2"},"sequence":{"accession":"P14406","fasta_url":"https://rest.uniprot.org/uniprotkb/P14406.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14406/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14406"}},"corpus_meta":[{"pmid":"23592244","id":"PMC_23592244","title":"Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23592244","citation_count":67,"is_preprint":false},{"pmid":"1327965","id":"PMC_1327965","title":"Tissue-specific expression and chromosome assignment of genes specifying two isoforms of subunit VIIa of human cytochrome c oxidase.","date":"1992","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/1327965","citation_count":64,"is_preprint":false},{"pmid":"8567667","id":"PMC_8567667","title":"Cytochrome c oxidase subunit VIIa liver isoform. 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Serie III, Sciences de la vie","url":"https://pubmed.ncbi.nlm.nih.gov/11803812","citation_count":1,"is_preprint":false},{"pmid":"40979532","id":"PMC_40979532","title":"Molecular pathogenesis of Alzheimer's disease onset in a mouse model: effects of cannabidiol treatment.","date":"2025","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/40979532","citation_count":1,"is_preprint":false},{"pmid":"41141600","id":"PMC_41141600","title":"Peripheral blood, lung and brain gene signatures in recovered and deceased patients with COVID-19.","date":"2025","source":"In silico pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41141600","citation_count":1,"is_preprint":false},{"pmid":"34233649","id":"PMC_34233649","title":"Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening.","date":"2021","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34233649","citation_count":1,"is_preprint":false},{"pmid":"17009529","id":"PMC_17009529","title":"[Construction of pGEX4T-1-Cox7a2 and expression, purification and identification of the recombinant protein].","date":"2006","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/17009529","citation_count":0,"is_preprint":false},{"pmid":"41639206","id":"PMC_41639206","title":"Integrative bioinformatics analyses of mitochondrial dysfunction-related genes in human non-obstructive azoospermia.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41639206","citation_count":0,"is_preprint":false},{"pmid":"41104785","id":"PMC_41104785","title":"Proteomic profiling of bone tissue reveals distinct pathways in men and women with osteoporosis.","date":"2025","source":"Age and ageing","url":"https://pubmed.ncbi.nlm.nih.gov/41104785","citation_count":0,"is_preprint":false},{"pmid":"41732265","id":"PMC_41732265","title":"Machine learning-driven identification of shared and disease-specific mitochondria-related genes in COPD, NSCLC, and NSCLC with COPD.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41732265","citation_count":0,"is_preprint":false},{"pmid":"41969564","id":"PMC_41969564","title":"Identification of myocardial contractility-related genes as regenerative targets and diagnostic biomarkers in coronary artery disease.","date":"2026","source":"Regenerative therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41969564","citation_count":0,"is_preprint":false},{"pmid":"41967724","id":"PMC_41967724","title":"Identifying mitochondria-related signatures for tuberculosis diagnosis through machine learning on single-cell transcriptomics data and experimental verification.","date":"2026","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41967724","citation_count":0,"is_preprint":false},{"pmid":"41950572","id":"PMC_41950572","title":"From clusters to clinic: An 8-gene signature combined with mucinous component stratifies benefit of anti-CTLA-4 addition to anti-PD-1 in dMMR/MSI-H metastatic colorectal cancer.","date":"2026","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/41950572","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28724,"output_tokens":2138,"usd":0.059121,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9165,"output_tokens":2624,"usd":0.055712,"stage2_stop_reason":"end_turn"},"total_usd":0.114833,"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\": 2021,\n      \"finding\": \"SILAC-based complexome profiling of SCAFI-knockout (SCAFIKO) HEK293T cells demonstrated that the majority (~70%) of human respirasomes contain COX7A2 (rather than COX7A2L/SCAFI) bridging Complex IV into the supercomplex, and these COX7A2-containing respirasomes persisted at roughly the same levels when SCAFI was knocked out, establishing COX7A2 as the predominant structural component linking Complex IV into respirasomes.\",\n      \"method\": \"SILAC-based complexome profiling, CRISPR-Cas9 knockout of SCAFI, native gel electrophoresis\",\n      \"journal\": \"Biochimica et biophysica acta. Bioenergetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SILAC complexome profiling with genetic knockout (CRISPR-Cas9), quantitative mass spectrometry, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"33727070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of Cox7a2 in TM3 mouse Leydig cells inhibited LH-induced testosterone secretion and suppressed StAR protein expression, while simultaneously increasing reactive oxygen species (ROS) activity, establishing that Cox7a2 modulates steroidogenesis at least in part through ROS-mediated suppression of StAR.\",\n      \"method\": \"Transient transfection overexpression, ELISA (testosterone), Western blot (StAR), fluorometric ROS assay\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal methods (ELISA, Western blot, ROS assay) in a single lab study with overexpression model\",\n      \"pmids\": [\"16752004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of Cox7a2 in TM3 mouse Leydig cells decreased phosphorylation of P70S6K and reduced StAR protein expression, thereby inhibiting LH-induced testosterone biosynthesis, implicating autophagy regulatory signaling (via P70S6K) as the mechanism downstream of Cox7a2.\",\n      \"method\": \"Transfection overexpression, ELISA (testosterone), Western blot (StAR, phospho-P70S6K)\",\n      \"journal\": \"Zhonghua nan ke xue = National journal of andrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression model, limited orthogonal validation, published in lower-tier journal\",\n      \"pmids\": [\"21548202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Fluorescent protein tagging and live-cell imaging showed that Cox7a2 localizes to mitochondria in TM3 Leydig cells, but co-expression of active Ras relocalized Cox7a2 away from mitochondria; expression of dominant-negative Ras restored mitochondrial localization, establishing that Ras signaling regulates the subcellular localization of Cox7a2.\",\n      \"method\": \"Fluorescent protein fusion (EYFP) live-cell imaging, dominant-negative Ras transfection\",\n      \"journal\": \"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single imaging method, no biochemical validation of the localization change or its functional consequence\",\n      \"pmids\": [\"22898835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genome-wide shRNA screen followed by siRNA validation identified Cox7a2 as a gene whose loss-of-function selectively induces apoptosis in HIV-infected macrophages but not in uninfected bystander macrophages; mechanistic follow-up indicated this selective killing involves enhanced ROS production through targeting of respiratory chain Complexes II and IV.\",\n      \"method\": \"Pooled shRNA genome-wide screen, siRNA knockdown validation, Annexin-V flow cytometry apoptosis assay\",\n      \"journal\": \"BMC infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased genome-wide screen with orthogonal siRNA validation and functional readout (apoptosis by flow cytometry), single lab\",\n      \"pmids\": [\"34233649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Northern blot and chromosome mapping of human-rodent cell hybrids established that COX7A2 (COXVIIa-L) encodes the ubiquitously expressed liver-type isoform of cytochrome c oxidase subunit VIIa, present in both muscle and non-muscle tissues, mapping to two loci on chromosomes 4 and 14.\",\n      \"method\": \"Northern blot, Southern blot hybridization of human-rodent somatic cell hybrids, cDNA cloning\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization with Northern and Southern blots, chromosome mapping, replicated across species\",\n      \"pmids\": [\"1327965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Promoter deletion analysis demonstrated that a 92-bp region flanking the 5′-end of the COX7AL gene drives most transcriptional activity and contains functional binding sites for NRF-1 and NRF-2 (nuclear respiratory factors) as well as Sp1 motifs; both NRF-1 and NRF-2 sites were shown to be functional, and interaction between the NRF-1 site and an upstream element contributes to expression.\",\n      \"method\": \"Promoter deletion/reporter assay, electrophoretic mobility shift assay (EMSA) for NRF-1 and NRF-2 binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter dissection with reporter assays and binding-site validation, single lab with multiple methods\",\n      \"pmids\": [\"8567667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional deletion of transcription factor E4F1 in mouse germ cells caused loss of the undifferentiated spermatogonial pool; ChIP/chromatin accessibility analysis showed E4F1 binds the promoter of Cox7a2 (among other respiratory chain genes), establishing E4F1 as a direct transcriptional regulator of Cox7a2 expression in spermatogonia.\",\n      \"method\": \"Conditional knockout mouse, single-cell RNA-seq, chromatin accessibility (ATAC-seq), ChIP-seq/promoter binding analysis\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined phenotype, chromatin binding data showing direct promoter occupancy, single lab\",\n      \"pmids\": [\"37749649\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COX7A2 (COXVIIa-L) is the ubiquitously expressed liver-type isoform of cytochrome c oxidase subunit VIIa whose promoter is driven by NRF-1, NRF-2, and Sp1 transcription factors (and directly by E4F1 in spermatogonia); it localizes to mitochondria and, as demonstrated by SILAC complexome profiling, predominantly bridges Complex IV into human respirasomes rather than into the minor SC III₂+IV supercomplex; in Leydig cells its overexpression suppresses LH-induced testosterone production by reducing StAR protein levels via ROS elevation and decreased P70S6K phosphorylation, and its loss-of-function selectively induces apoptosis in HIV-infected macrophages through enhanced ROS production at the respiratory chain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COX7A2 (COXVIIa-L) is the ubiquitously expressed liver-type isoform of cytochrome c oxidase subunit VIIa, present across muscle and non-muscle tissues [#5], and functions as the predominant structural component bridging Complex IV into respiratory chain supercomplexes: SILAC complexome profiling established that the majority of human respirasomes incorporate COX7A2 rather than COX7A2L/SCAFI, and these COX7A2-containing assemblies persist independently of SCAFI [#0]. Transcription of COX7A2 is governed by the mitochondrial biogenesis regulators NRF-1 and NRF-2 together with Sp1 acting on a compact proximal promoter [#6], and in spermatogonia it is a direct target of E4F1, whose loss depletes the undifferentiated spermatogonial pool [#7]. Beyond its core role in oxidative phosphorylation, modulation of COX7A2 levels alters reactive oxygen species output at the respiratory chain: its overexpression in Leydig cells suppresses LH-induced testosterone synthesis by lowering StAR protein through ROS elevation [#1], while its loss-of-function selectively triggers apoptosis in HIV-infected macrophages via enhanced ROS production at Complexes II and IV [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the identity and tissue distribution of COX7A2 as a distinct cytochrome c oxidase subunit VIIa isoform, defining the gene whose mechanism would later be dissected.\",\n      \"evidence\": \"cDNA cloning, Northern/Southern blot, and chromosome mapping in human-rodent cell hybrids\",\n      \"pmids\": [\"1327965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address how the isoform integrates into the holoenzyme or supercomplexes\", \"Multiple mapped loci left genomic organization ambiguous\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved how COX7A2 expression is controlled, linking the gene to the nuclear respiratory factor program that coordinates mitochondrial biogenesis.\",\n      \"evidence\": \"Promoter deletion/reporter assays and EMSA showing functional NRF-1, NRF-2, and Sp1 sites in a 92-bp proximal promoter\",\n      \"pmids\": [\"8567667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test the promoter in tissue-specific contexts\", \"Functional consequence of NRF binding on respiratory capacity not measured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected COX7A2 levels to steroidogenic output, showing the subunit can act as a ROS-dependent suppressor of testosterone biosynthesis.\",\n      \"evidence\": \"Overexpression in TM3 Leydig cells with testosterone ELISA, StAR Western blot, and fluorometric ROS assay\",\n      \"pmids\": [\"16752004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression model only; loss-of-function effect on steroidogenesis untested\", \"Causal chain from ROS to StAR suppression not directly demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the steroidogenic mechanism by placing P70S6K signaling downstream of COX7A2 in the suppression of StAR.\",\n      \"evidence\": \"Overexpression in TM3 Leydig cells with phospho-P70S6K and StAR Western blots and testosterone ELISA\",\n      \"pmids\": [\"21548202\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression model with limited orthogonal validation in a lower-tier journal\", \"Direct link between P70S6K phosphorylation and StAR levels not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Probed whether COX7A2 subcellular localization is dynamically regulated, implicating Ras signaling in directing it away from mitochondria.\",\n      \"evidence\": \"EYFP fusion live-cell imaging with active and dominant-negative Ras in TM3 Leydig cells\",\n      \"pmids\": [\"22898835\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single imaging method with no biochemical confirmation of relocalization\", \"Functional consequence of the localization change not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the core structural role of COX7A2 in respiratory chain organization, showing it, not SCAFI, is the predominant bridge of Complex IV into respirasomes.\",\n      \"evidence\": \"SILAC complexome profiling with CRISPR-Cas9 SCAFI knockout and native gel electrophoresis in HEK293T cells\",\n      \"pmids\": [\"33727070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the COX7A2-respirasome interface not resolved\", \"Physiological consequence of COX7A2 loss on supercomplex assembly not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a context-dependent vulnerability whereby loss of COX7A2 selectively kills HIV-infected cells through respiratory-chain ROS.\",\n      \"evidence\": \"Genome-wide shRNA screen with siRNA validation and Annexin-V flow cytometry in HIV-infected macrophages\",\n      \"pmids\": [\"34233649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking COX7A2 loss to Complex II/IV ROS not biochemically dissected\", \"Why selectivity is restricted to infected cells unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a tissue-specific transcriptional regulator, placing COX7A2 within an E4F1-driven respiratory gene program required for spermatogonial maintenance.\",\n      \"evidence\": \"Conditional E4F1 knockout mouse with scRNA-seq, ATAC-seq, and ChIP-seq promoter occupancy analysis\",\n      \"pmids\": [\"37749649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not isolate COX7A2's individual contribution to the spermatogonial phenotype\", \"Direct functional rescue by COX7A2 not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COX7A2's role in respirasome bridging mechanistically connects to its ROS-modulating effects on steroidogenesis and infected-cell apoptosis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of COX7A2 within the respirasome\", \"Unclear whether ROS phenotypes stem from altered supercomplex assembly\", \"No loss-of-function study of COX7A2 in steroidogenic tissue\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1430728\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"respirasome (respiratory chain supercomplex)\", \"cytochrome c oxidase (Complex IV)\"],\n    \"partners\": [\"COX7A2L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}