{"gene":"MZT2B","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2025,"finding":"MZT2B knockdown or CRISPR/Cas9 knockout in NSCLC cells impaired mitochondrial respiration, reducing oxygen consumption rates, ATP production, mitochondrial membrane potential, and cellular redox homeostasis (ROS, GSH/GSSG ratio), and downregulated COX5B (cytochrome c oxidase subunit 5B) expression; restoring COX5B or increasing glucose concentration rescued the anti-proliferative effects of MZT2B depletion, placing COX5B downstream of MZT2B in mitochondrial function regulation.","method":"shRNA knockdown and CRISPR/Cas9 knockout in NSCLC cell lines; mitochondrial respiration assays (OCR, ATP, membrane potential, ROS); rescue experiments with COX5B overexpression and glucose supplementation; subcutaneous xenograft mouse models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (KO, respiration, in vivo xenograft, rescue) in a single lab; no structural or in vitro reconstitution","pmids":["41213905"],"is_preprint":false},{"year":2025,"finding":"Genome-wide CRISPR knockout screen identified synthetic lethality between FBXO42 mutation and mutations in γ-tubulin ring complex proteins MZT1 and MZT2B, indicating that MZT2B functions in centrosome and/or mitotic spindle assembly and that cells with defects in this pathway are hypersensitive to FBXO42 loss.","method":"Genome-wide CRISPR knockout screen (genetic epistasis/synthetic lethality)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single screen result from preprint, no direct biochemical characterization of MZT2B in this context","pmids":["bio_10.1101_2025.04.22.649889"],"is_preprint":true}],"current_model":"MZT2B (MOZART2B) is a mitotic spindle organizing protein (γ-TuRC component) that also critically supports mitochondrial function in cancer cells by promoting COX5B expression, thereby sustaining oxidative phosphorylation, ATP production, and redox homeostasis; genetic loss of MZT2B impairs NSCLC cell proliferation and tumor growth, and synthetic lethality screens place MZT2B in centrosome/spindle assembly pathways alongside MZT1."},"narrative":{"mechanistic_narrative":"MZT2B is a γ-tubulin ring complex (γ-TuRC) component implicated in centrosome and mitotic spindle assembly, identified through synthetic lethality with FBXO42 loss alongside the related γ-TuRC protein MZT1 [PMID:bio_10.1101_2025.04.22.649889]. Beyond this spindle-organizing role, MZT2B supports mitochondrial function in non-small-cell lung cancer cells: its depletion reduces oxygen consumption, ATP production, mitochondrial membrane potential, and disrupts redox homeostasis, with downregulation of the cytochrome c oxidase subunit COX5B; re-expression of COX5B or glucose supplementation rescues the anti-proliferative effect, placing COX5B downstream of MZT2B in sustaining oxidative phosphorylation and tumor cell proliferation [PMID:41213905]. Beyond these findings, no structural mechanism or direct biochemical characterization of MZT2B has been established in the available corpus.","teleology":[{"year":2025,"claim":"Whether MZT2B has a functional role beyond a presumed structural one was unknown; loss-of-function in cancer cells revealed it sustains mitochondrial oxidative phosphorylation via COX5B.","evidence":"shRNA/CRISPR knockout in NSCLC lines with respiration assays, redox measurements, COX5B/glucose rescue, and xenografts","pmids":["41213905"],"confidence":"Medium","gaps":["mechanism by which MZT2B controls COX5B expression is not defined","no structural or in vitro reconstitution of MZT2B","link between the spindle role and mitochondrial role unresolved"]},{"year":2025,"claim":"The pathway context of MZT2B was uncharacterized; a genome-wide screen placed it in centrosome/spindle assembly through synthetic lethality with FBXO42 alongside MZT1.","evidence":"genome-wide CRISPR knockout synthetic-lethality screen (preprint)","pmids":["bio_10.1101_2025.04.22.649889"],"confidence":"Low","gaps":["single screen result, not independently confirmed","no direct biochemical demonstration of MZT2B in γ-TuRC in this study","mechanism of FBXO42 dependence unknown"]},{"year":null,"claim":"How MZT2B mechanistically connects its γ-TuRC/spindle association to control of COX5B and mitochondrial respiration remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no structural model of MZT2B","no direct molecular activity assigned","mechanism coupling spindle function and mitochondrial regulation unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["MZT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NZ67","full_name":"Mitotic-spindle organizing protein 2B","aliases":["Mitotic-spindle organizing protein associated with a ring of gamma-tubulin 2B"],"length_aa":158,"mass_kda":16.2,"function":"Required for the recruitment and the assembly of the gamma-tubulin ring complex (gTuRC) at the centrosome (PubMed:20360068, PubMed:39321809). The gTuRC regulates the minus-end nucleation of alpha-beta tubulin heterodimers that grow into microtubule protafilaments, a critical step in centrosome duplication and spindle formation (PubMed:39321809)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q6NZ67/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MZT2B","classification":"Not Classified","n_dependent_lines":108,"n_total_lines":1047,"dependency_fraction":0.10315186246418338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MZT2B","total_profiled":1310},"omim":[{"mim_id":"613450","title":"MITOTIC SPINDLE-ORGANIZING PROTEIN 2B; MZT2B","url":"https://www.omim.org/entry/613450"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MZT2B"},"hgnc":{"alias_symbol":["FLJ14346","MOZART2B"],"prev_symbol":["FAM128B"]},"alphafold":{"accession":"Q6NZ67","domains":[{"cath_id":"-","chopping":"18-82","consensus_level":"high","plddt":83.5058,"start":18,"end":82}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NZ67","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NZ67-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NZ67-F1-predicted_aligned_error_v6.png","plddt_mean":63.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MZT2B","jax_strain_url":"https://www.jax.org/strain/search?query=MZT2B"},"sequence":{"accession":"Q6NZ67","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NZ67.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NZ67/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NZ67"}},"corpus_meta":[{"pmid":"35004283","id":"PMC_35004283","title":"m6A Regulator Expression Segregates Meningiomas Into Biologically Distinct Subtypes.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35004283","citation_count":4,"is_preprint":false},{"pmid":"41213905","id":"PMC_41213905","title":"MZT2B promotes malignant phenotypes in NSCLC cells by enhancing mitochondrial function and COX5B expression.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41213905","citation_count":0,"is_preprint":false},{"pmid":"41661231","id":"PMC_41661231","title":"RNAseq-based meta-analyses revealed tumor suppressor-inducer fusion events in liver, oral, and ovarian cancer in the Indian population: a cancer cell surviving mechanism.","date":"2026","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/41661231","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.22.649889","title":"The regulation of Protein Phosphatase 4 by FBXO42 is required for cancer cell survival","date":"2025-04-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.22.649889","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4690,"output_tokens":697,"usd":0.012263,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7094,"output_tokens":1119,"usd":0.031723,"stage2_stop_reason":"end_turn"},"total_usd":0.043986,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"MZT2B knockdown or CRISPR/Cas9 knockout in NSCLC cells impaired mitochondrial respiration, reducing oxygen consumption rates, ATP production, mitochondrial membrane potential, and cellular redox homeostasis (ROS, GSH/GSSG ratio), and downregulated COX5B (cytochrome c oxidase subunit 5B) expression; restoring COX5B or increasing glucose concentration rescued the anti-proliferative effects of MZT2B depletion, placing COX5B downstream of MZT2B in mitochondrial function regulation.\",\n      \"method\": \"shRNA knockdown and CRISPR/Cas9 knockout in NSCLC cell lines; mitochondrial respiration assays (OCR, ATP, membrane potential, ROS); rescue experiments with COX5B overexpression and glucose supplementation; subcutaneous xenograft mouse models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (KO, respiration, in vivo xenograft, rescue) in a single lab; no structural or in vitro reconstitution\",\n      \"pmids\": [\"41213905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genome-wide CRISPR knockout screen identified synthetic lethality between FBXO42 mutation and mutations in γ-tubulin ring complex proteins MZT1 and MZT2B, indicating that MZT2B functions in centrosome and/or mitotic spindle assembly and that cells with defects in this pathway are hypersensitive to FBXO42 loss.\",\n      \"method\": \"Genome-wide CRISPR knockout screen (genetic epistasis/synthetic lethality)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single screen result from preprint, no direct biochemical characterization of MZT2B in this context\",\n      \"pmids\": [\"bio_10.1101_2025.04.22.649889\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MZT2B (MOZART2B) is a mitotic spindle organizing protein (γ-TuRC component) that also critically supports mitochondrial function in cancer cells by promoting COX5B expression, thereby sustaining oxidative phosphorylation, ATP production, and redox homeostasis; genetic loss of MZT2B impairs NSCLC cell proliferation and tumor growth, and synthetic lethality screens place MZT2B in centrosome/spindle assembly pathways alongside MZT1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MZT2B is a γ-tubulin ring complex (γ-TuRC) component implicated in centrosome and mitotic spindle assembly, identified through synthetic lethality with FBXO42 loss alongside the related γ-TuRC protein MZT1 [#1]. Beyond this spindle-organizing role, MZT2B supports mitochondrial function in non-small-cell lung cancer cells: its depletion reduces oxygen consumption, ATP production, mitochondrial membrane potential, and disrupts redox homeostasis, with downregulation of the cytochrome c oxidase subunit COX5B; re-expression of COX5B or glucose supplementation rescues the anti-proliferative effect, placing COX5B downstream of MZT2B in sustaining oxidative phosphorylation and tumor cell proliferation [#0]. Beyond these findings, no structural mechanism or direct biochemical characterization of MZT2B has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether MZT2B has a functional role beyond a presumed structural one was unknown; loss-of-function in cancer cells revealed it sustains mitochondrial oxidative phosphorylation via COX5B.\",\n      \"evidence\": \"shRNA/CRISPR knockout in NSCLC lines with respiration assays, redox measurements, COX5B/glucose rescue, and xenografts\",\n      \"pmids\": [\"41213905\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"mechanism by which MZT2B controls COX5B expression is not defined\", \"no structural or in vitro reconstitution of MZT2B\", \"link between the spindle role and mitochondrial role unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The pathway context of MZT2B was uncharacterized; a genome-wide screen placed it in centrosome/spindle assembly through synthetic lethality with FBXO42 alongside MZT1.\",\n      \"evidence\": \"genome-wide CRISPR knockout synthetic-lethality screen (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.22.649889\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"single screen result, not independently confirmed\", \"no direct biochemical demonstration of MZT2B in γ-TuRC in this study\", \"mechanism of FBXO42 dependence unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MZT2B mechanistically connects its γ-TuRC/spindle association to control of COX5B and mitochondrial respiration remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"no structural model of MZT2B\", \"no direct molecular activity assigned\", \"mechanism coupling spindle function and mitochondrial regulation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"MZT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":1,"faith_total":1,"faith_pct":100.0}}