{"gene":"CCDC90B","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2019,"finding":"CCDC90B adopts a trimeric membrane-anchored architecture with a head-neck-stalk-anchor organization; crystal structure of the human CCDC90B head domain was determined, revealing it as the most widespread head type among a conserved family of prokaryotic and eukaryotic organelle proteins.","method":"Crystal structure determination; sequence analysis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure solved with functional domain characterization in a single rigorous structural study","pmids":["30612859"],"is_preprint":false},{"year":2019,"finding":"The head domain of CCDC90B (and its paralog MCUR1) directly interacts with the mitochondrial calcium uniporter (MCU) and is destabilized upon Ca2+ binding, identifying the conserved head domain as the functional mediator of MCU interaction.","method":"Direct binding assay using MCUR1 (paralog) as functional model; domain mutagenesis/deletion studies; structural analysis","journal":"Structure","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction established using MCUR1 paralog as proxy with domain-level dissection; Ca2+-dependent destabilization shown, but functional data for CCDC90B itself is inferred from paralogy","pmids":["30612859"],"is_preprint":false},{"year":2026,"finding":"Uric acid (UA) binds directly to CCDC90B, causing its accumulation within cells, which exacerbates mitochondrial calcium influx and leads to mitochondrial quality control (MQC) imbalance and stem Leydig cell senescence; AAV8-mediated CCDC90B overexpression rescues senescence and restores testosterone in transgenic mice.","method":"Single-cell RNA sequencing; direct UA-CCDC90B binding assay; organoid and transgenic mouse models; AAV8 gene therapy rescue experiment","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple in vivo and organoid methods in a single lab study; direct binding claim requires full-text confirmation of binding assay rigor","pmids":["42242294"],"is_preprint":false},{"year":2025,"finding":"MCUR1 and CCDC90B form a hetero-oligomeric coiled-coil complex at the inner mitochondrial membrane; stability of this complex depends on MCUR1, such that MCUR1 loss exerts a dominant-negative effect on CCDC90B. Deletion of both proteins in S. pombe (which lacks the mitochondrial calcium uniporter complex) impairs lipid and amino acid metabolism and causes nitrogen source-dependent growth defects rescued by human MCUR1, redefining the complex as a transmembrane scaffold for mitochondrial protein complex integrity and metabolic homeostasis.","method":"Genetic deletion in S. pombe; patient-derived fibroblast studies; serum metabolomics; epistasis/rescue with human MCUR1 expression; proliferation and migration assays; autophagy measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (yeast genetics, patient cells, metabolomics, rescue experiments) in a single preprint study; not yet peer-reviewed","pmids":["bio_10.1101_2025.10.14.682030"],"is_preprint":true},{"year":2020,"finding":"CCDC90B localizes to mitochondria, as validated by overexpression in 293T cells and immunofluorescence staining.","method":"Overexpression in 293T cells; immunofluorescence staining","journal":"Journal of proteome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (immunofluorescence of overexpressed protein), no functional consequence linked","pmids":["33089979"],"is_preprint":false}],"current_model":"CCDC90B is an inner mitochondrial membrane protein with a conserved trimeric head-neck-stalk-anchor architecture; its head domain mediates direct interaction with the mitochondrial calcium uniporter (MCU) and is destabilized by Ca2+ binding, while CCDC90B forms a hetero-oligomeric scaffold complex with its paralog MCUR1 (stability dependent on MCUR1) that maintains mitochondrial protein complex integrity and metabolic homeostasis; additionally, uric acid binding to CCDC90B causes its accumulation and exacerbates mitochondrial calcium influx, leading to mitochondrial quality control imbalance."},"narrative":{"mechanistic_narrative":"CCDC90B is a mitochondrial protein that functions as a conserved structural scaffold at the inner mitochondrial membrane, supporting mitochondrial complex integrity and metabolic homeostasis [PMID:30612859, PMID:33089979]. It adopts a trimeric head-neck-stalk-anchor architecture, and its head domain—the most widespread head type among a conserved family of prokaryotic and eukaryotic organelle proteins—directly engages the mitochondrial calcium uniporter (MCU) in a manner destabilized by Ca2+ binding [PMID:30612859]. CCDC90B forms a hetero-oligomeric coiled-coil complex with its paralog MCUR1 whose stability depends on MCUR1, and loss of this scaffold impairs lipid and amino acid metabolism, establishing the complex as a transmembrane scaffold for mitochondrial protein complex integrity even in systems lacking the uniporter [PMID:bio_10.1101_2025.10.14.682030]. Direct binding of uric acid to CCDC90B drives its cellular accumulation, exacerbating mitochondrial calcium influx and disrupting mitochondrial quality control, with CCDC90B overexpression rescuing stem Leydig cell senescence and restoring testosterone in mice [PMID:42242294].","teleology":[{"year":2019,"claim":"Establishing the structural architecture of CCDC90B answered how this protein is organized and placed it within a conserved organelle protein family, defining its functional head domain.","evidence":"Crystal structure determination of the human head domain plus sequence analysis","pmids":["30612859"],"confidence":"High","gaps":["Structure of the full-length trimer including neck-stalk-anchor not resolved","Functional consequence of the architecture not directly tested for CCDC90B"]},{"year":2019,"claim":"Showing the head domain directly binds MCU and is destabilized by Ca2+ identified the molecular interface coupling CCDC90B to the calcium uniporter, though CCDC90B-specific binding was inferred from its paralog MCUR1.","evidence":"Direct binding assays using MCUR1 as a functional proxy, domain mutagenesis, and structural analysis","pmids":["30612859"],"confidence":"Medium","gaps":["CCDC90B-MCU binding inferred from MCUR1 paralog rather than measured directly","Functional consequence of Ca2+-dependent destabilization on uniporter activity not established"]},{"year":2020,"claim":"Localization studies confirmed CCDC90B resides in mitochondria, anchoring later functional work in the correct compartment.","evidence":"Overexpression in 293T cells with immunofluorescence staining","pmids":["33089979"],"confidence":"Low","gaps":["Single method on overexpressed protein, no endogenous validation or submitochondrial resolution","No functional consequence linked to localization"]},{"year":2025,"claim":"Defining the MCUR1-CCDC90B hetero-oligomeric complex and its MCUR1-dependent stability reframed CCDC90B as a transmembrane metabolic scaffold rather than a uniporter-only accessory, since deletion in uniporter-lacking S. pombe still impaired lipid and amino acid metabolism.","evidence":"Genetic deletion in S. pombe, patient-derived fibroblasts, serum metabolomics, and rescue with human MCUR1 (preprint)","pmids":["bio_10.1101_2025.10.14.682030"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Molecular mechanism by which the scaffold maintains complex integrity unresolved","Direct metabolic substrate or pathway target not identified"]},{"year":2026,"claim":"Identifying uric acid as a direct CCDC90B ligand connected the protein to mitochondrial quality control and cellular senescence, providing an in vivo gain-of-function rescue.","evidence":"Single-cell RNA sequencing, direct UA-binding assay, organoid and transgenic mouse models, AAV8 gene-therapy rescue","pmids":["42242294"],"confidence":"Medium","gaps":["Binding-assay rigor and affinity require full-text confirmation","Mechanism linking uric acid binding to calcium influx not resolved","Single-lab study without independent replication"]},{"year":null,"claim":"How the CCDC90B-MCUR1 scaffold mechanistically maintains mitochondrial complex integrity and couples to calcium handling and metabolic homeostasis remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined molecular mechanism linking scaffold to specific protein complexes","Direct CCDC90B-MCU binding never measured independent of MCUR1","Physiological regulation of CCDC90B abundance beyond uric acid unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3]}],"complexes":["MCUR1-CCDC90B hetero-oligomeric scaffold complex"],"partners":["MCUR1","MCU"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZT6","full_name":"Coiled-coil domain-containing protein 90B, mitochondrial","aliases":[],"length_aa":254,"mass_kda":29.5,"function":"","subcellular_location":"Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q9GZT6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC90B","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSPA4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCDC90B","total_profiled":1310},"omim":[{"mim_id":"620753","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 90B; CCDC90B","url":"https://www.omim.org/entry/620753"},{"mim_id":"616952","title":"MITOCHONDRIAL CALCIUM UNIPORTER REGULATOR 1; MCUR1","url":"https://www.omim.org/entry/616952"}],"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/CCDC90B"},"hgnc":{"alias_symbol":["MDS025","MDS011"],"prev_symbol":[]},"alphafold":{"accession":"Q9GZT6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZT6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZT6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZT6-F1-predicted_aligned_error_v6.png","plddt_mean":81.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC90B","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC90B"},"sequence":{"accession":"Q9GZT6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZT6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZT6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZT6"}},"corpus_meta":[{"pmid":"30612859","id":"PMC_30612859","title":"Characterization of MCU-Binding Proteins MCUR1 and CCDC90B - Representatives of a Protein Family Conserved in Prokaryotes and Eukaryotic Organelles.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/30612859","citation_count":20,"is_preprint":false},{"pmid":"36292606","id":"PMC_36292606","title":"A Comparative Cross-Platform Analysis to Identify Potential Biomarker Genes for Evaluation of Teratozoospermia and Azoospermia.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36292606","citation_count":5,"is_preprint":false},{"pmid":"33089979","id":"PMC_33089979","title":"Bioinformatic Prediction of Gene Ontology Terms of Uncharacterized Proteins from Chromosome 11.","date":"2020","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/33089979","citation_count":4,"is_preprint":false},{"pmid":"39087007","id":"PMC_39087007","title":"Causal relationship between mitochondrial-associated proteins and cerebral aneurysms: a Mendelian randomization study.","date":"2024","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39087007","citation_count":3,"is_preprint":false},{"pmid":"42242294","id":"PMC_42242294","title":"High Uric Acid Promotes Stem Leydig Cell Senescence by CCDC90B Mediates Mitochondrial Quality Control Imbalance.","date":"2026","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/42242294","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.14.682030","title":"MCUR1–CCDC90B complex is a conserved mitochondrial scaffold regulating metabolic homeostasis","date":"2025-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.14.682030","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5530,"output_tokens":1278,"usd":0.01788,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7969,"output_tokens":2095,"usd":0.04611,"stage2_stop_reason":"end_turn"},"total_usd":0.06399,"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\": 2019,\n      \"finding\": \"CCDC90B adopts a trimeric membrane-anchored architecture with a head-neck-stalk-anchor organization; crystal structure of the human CCDC90B head domain was determined, revealing it as the most widespread head type among a conserved family of prokaryotic and eukaryotic organelle proteins.\",\n      \"method\": \"Crystal structure determination; sequence analysis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure solved with functional domain characterization in a single rigorous structural study\",\n      \"pmids\": [\"30612859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The head domain of CCDC90B (and its paralog MCUR1) directly interacts with the mitochondrial calcium uniporter (MCU) and is destabilized upon Ca2+ binding, identifying the conserved head domain as the functional mediator of MCU interaction.\",\n      \"method\": \"Direct binding assay using MCUR1 (paralog) as functional model; domain mutagenesis/deletion studies; structural analysis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction established using MCUR1 paralog as proxy with domain-level dissection; Ca2+-dependent destabilization shown, but functional data for CCDC90B itself is inferred from paralogy\",\n      \"pmids\": [\"30612859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Uric acid (UA) binds directly to CCDC90B, causing its accumulation within cells, which exacerbates mitochondrial calcium influx and leads to mitochondrial quality control (MQC) imbalance and stem Leydig cell senescence; AAV8-mediated CCDC90B overexpression rescues senescence and restores testosterone in transgenic mice.\",\n      \"method\": \"Single-cell RNA sequencing; direct UA-CCDC90B binding assay; organoid and transgenic mouse models; AAV8 gene therapy rescue experiment\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple in vivo and organoid methods in a single lab study; direct binding claim requires full-text confirmation of binding assay rigor\",\n      \"pmids\": [\"42242294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MCUR1 and CCDC90B form a hetero-oligomeric coiled-coil complex at the inner mitochondrial membrane; stability of this complex depends on MCUR1, such that MCUR1 loss exerts a dominant-negative effect on CCDC90B. Deletion of both proteins in S. pombe (which lacks the mitochondrial calcium uniporter complex) impairs lipid and amino acid metabolism and causes nitrogen source-dependent growth defects rescued by human MCUR1, redefining the complex as a transmembrane scaffold for mitochondrial protein complex integrity and metabolic homeostasis.\",\n      \"method\": \"Genetic deletion in S. pombe; patient-derived fibroblast studies; serum metabolomics; epistasis/rescue with human MCUR1 expression; proliferation and migration assays; autophagy measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (yeast genetics, patient cells, metabolomics, rescue experiments) in a single preprint study; not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.682030\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCDC90B localizes to mitochondria, as validated by overexpression in 293T cells and immunofluorescence staining.\",\n      \"method\": \"Overexpression in 293T cells; immunofluorescence staining\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (immunofluorescence of overexpressed protein), no functional consequence linked\",\n      \"pmids\": [\"33089979\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC90B is an inner mitochondrial membrane protein with a conserved trimeric head-neck-stalk-anchor architecture; its head domain mediates direct interaction with the mitochondrial calcium uniporter (MCU) and is destabilized by Ca2+ binding, while CCDC90B forms a hetero-oligomeric scaffold complex with its paralog MCUR1 (stability dependent on MCUR1) that maintains mitochondrial protein complex integrity and metabolic homeostasis; additionally, uric acid binding to CCDC90B causes its accumulation and exacerbates mitochondrial calcium influx, leading to mitochondrial quality control imbalance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCDC90B is a mitochondrial protein that functions as a conserved structural scaffold at the inner mitochondrial membrane, supporting mitochondrial complex integrity and metabolic homeostasis [#0, #4]. It adopts a trimeric head-neck-stalk-anchor architecture, and its head domain—the most widespread head type among a conserved family of prokaryotic and eukaryotic organelle proteins—directly engages the mitochondrial calcium uniporter (MCU) in a manner destabilized by Ca2+ binding [#0, #1]. CCDC90B forms a hetero-oligomeric coiled-coil complex with its paralog MCUR1 whose stability depends on MCUR1, and loss of this scaffold impairs lipid and amino acid metabolism, establishing the complex as a transmembrane scaffold for mitochondrial protein complex integrity even in systems lacking the uniporter [#3]. Direct binding of uric acid to CCDC90B drives its cellular accumulation, exacerbating mitochondrial calcium influx and disrupting mitochondrial quality control, with CCDC90B overexpression rescuing stem Leydig cell senescence and restoring testosterone in mice [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing the structural architecture of CCDC90B answered how this protein is organized and placed it within a conserved organelle protein family, defining its functional head domain.\",\n      \"evidence\": \"Crystal structure determination of the human head domain plus sequence analysis\",\n      \"pmids\": [\"30612859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of the full-length trimer including neck-stalk-anchor not resolved\",\n        \"Functional consequence of the architecture not directly tested for CCDC90B\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing the head domain directly binds MCU and is destabilized by Ca2+ identified the molecular interface coupling CCDC90B to the calcium uniporter, though CCDC90B-specific binding was inferred from its paralog MCUR1.\",\n      \"evidence\": \"Direct binding assays using MCUR1 as a functional proxy, domain mutagenesis, and structural analysis\",\n      \"pmids\": [\"30612859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"CCDC90B-MCU binding inferred from MCUR1 paralog rather than measured directly\",\n        \"Functional consequence of Ca2+-dependent destabilization on uniporter activity not established\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localization studies confirmed CCDC90B resides in mitochondria, anchoring later functional work in the correct compartment.\",\n      \"evidence\": \"Overexpression in 293T cells with immunofluorescence staining\",\n      \"pmids\": [\"33089979\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single method on overexpressed protein, no endogenous validation or submitochondrial resolution\",\n        \"No functional consequence linked to localization\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining the MCUR1-CCDC90B hetero-oligomeric complex and its MCUR1-dependent stability reframed CCDC90B as a transmembrane metabolic scaffold rather than a uniporter-only accessory, since deletion in uniporter-lacking S. pombe still impaired lipid and amino acid metabolism.\",\n      \"evidence\": \"Genetic deletion in S. pombe, patient-derived fibroblasts, serum metabolomics, and rescue with human MCUR1 (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.682030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not yet peer-reviewed\",\n        \"Molecular mechanism by which the scaffold maintains complex integrity unresolved\",\n        \"Direct metabolic substrate or pathway target not identified\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identifying uric acid as a direct CCDC90B ligand connected the protein to mitochondrial quality control and cellular senescence, providing an in vivo gain-of-function rescue.\",\n      \"evidence\": \"Single-cell RNA sequencing, direct UA-binding assay, organoid and transgenic mouse models, AAV8 gene-therapy rescue\",\n      \"pmids\": [\"42242294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding-assay rigor and affinity require full-text confirmation\",\n        \"Mechanism linking uric acid binding to calcium influx not resolved\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the CCDC90B-MCUR1 scaffold mechanistically maintains mitochondrial complex integrity and couples to calcium handling and metabolic homeostasis remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No defined molecular mechanism linking scaffold to specific protein complexes\",\n        \"Direct CCDC90B-MCU binding never measured independent of MCUR1\",\n        \"Physiological regulation of CCDC90B abundance beyond uric acid unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"MCUR1-CCDC90B hetero-oligomeric scaffold complex\"\n    ],\n    \"partners\": [\n      \"MCUR1\",\n      \"MCU\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}