{"gene":"MRPS15","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2024,"finding":"MRPS15 is found as a component of cytosolic ribosomes (polysomes) in stressed human cardiomyocytes, not only in mitochondrial ribosomes. Under ER stress induced by tunicamycin, MRPS15 levels in cytosolic polysomes increase dramatically. Its interaction with cytosolic ribosomal proteins was confirmed by proximity ligation assay and immunoprecipitation. Knockdown or overexpression of MRPS15 demonstrated its role as an activator of IRES-dependent translation. Polysome profiling after anti-MRPS15 immunoprecipitation showed that 'MRPS15 ribosomes' are specialized in translating mRNAs involved in the unfolded protein response.","method":"Mass spectrometry of translating ribosome composition, proximity ligation assay, immunoprecipitation, knockdown/overexpression functional assays, polysome profiling with anti-MRPS15 immunoprecipitation","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (MS, PLA, Co-IP, polysome profiling, KD/OE) in a single focused study establishing a novel cytosolic ribosomal role","pmids":["38542224"],"is_preprint":false},{"year":2026,"finding":"Knockdown of Mrps15 (together with Mrps21) in cardiomyocytes inhibits mitochondrial translation, leading to depolarization of mitochondrial membrane potential, impaired mitochondrial respiration, reduced membrane translocation of nuclear-encoded mitochondrial proteins, and mitochondrial ROS production associated with reduced mitochondrial glutaredoxin-2. Overexpression of Mrps15/Mrps21 restores cardiac function in hypertensive heart disease mice. The transcription factor Zhx1 promotes transcription of Mrps15/Mrps21; combined silencing of Mrps15/Mrps21 compromised the protective effect of Zhx1, placing Mrps15 downstream of Zhx1 in this pathway.","method":"Knockdown and overexpression in cardiomyocytes, mitochondrial membrane potential assay, mitochondrial respiration assay, mouse HHD model (L-NAME gavage), Zhx1 activator treatment, epistasis by combined Mrps15/Mrps21 silencing","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and genetic epistasis in a single lab study, but no in vitro reconstitution or structural data","pmids":["42162768"],"is_preprint":false},{"year":2026,"finding":"In C. elegans, a point mutation in MRPS-15 (a mitoribosomal small subunit protein) acts as a suppressor of LONP-1 deficiency, restoring mitochondrial function and development. This suppressor mutation is proposed to enhance oxidative phosphorylation complex assembly by slowing mitochondrial translation, placing MRPS-15 as a functional component of the mitoribosome whose activity modulates OXPHOS complex assembly downstream of LONP-1.","method":"Forward genetic suppressor screen in C. elegans lonp-1 mutants, identification of suppressor mutations in mitoribosomal protein genes, measurement of oxidative phosphorylation restoration","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis via forward suppressor screen in a model organism, single study, preprint not yet peer-reviewed","pmids":["41648325"],"is_preprint":true}],"current_model":"MRPS15 (uS15m) is a mitochondrial ribosomal small subunit protein required for mitochondrial translation and OXPHOS complex assembly; under cellular stress, it additionally localizes to cytosolic polysomes where it activates IRES-dependent translation of unfolded protein response mRNAs, and its mitochondrial function is transcriptionally regulated by the zinc-finger protein Zhx1."},"narrative":{"mechanistic_narrative":"MRPS15 (uS15m) is a small-subunit mitoribosomal protein required for mitochondrial translation and the downstream assembly of oxidative phosphorylation complexes [PMID:42162768, PMID:41648325]. Loss of MRPS15 (with MRPS21) in cardiomyocytes inhibits mitochondrial translation, depolarizes the mitochondrial membrane potential, impairs respiration, reduces import of nuclear-encoded mitochondrial proteins, and triggers mitochondrial ROS associated with loss of glutaredoxin-2; its transcription is driven by the zinc-finger factor Zhx1, and MRPS15/MRPS21 act downstream of Zhx1 to confer cardioprotection in hypertensive heart disease [PMID:42162768]. In C. elegans, a point mutation in the MRPS-15 ortholog suppresses LONP-1 deficiency by slowing mitochondrial translation and restoring OXPHOS complex assembly, identifying mitoribosomal translation rate as a tunable determinant of complex biogenesis [PMID:41648325]. Beyond its canonical mitoribosomal role, MRPS15 is recruited to cytosolic polysomes during ER stress, where it interacts with cytosolic ribosomal proteins and activates IRES-dependent translation of unfolded protein response mRNAs, defining a stress-induced extra-mitochondrial function [PMID:38542224].","teleology":[{"year":2024,"claim":"Whether MRPS15 functions exclusively within mitoribosomes was unknown; this work established a stress-induced cytosolic role in selective translation, expanding the protein's functional repertoire beyond mitochondria.","evidence":"Mass spectrometry of translating ribosomes, proximity ligation assay, Co-IP, knockdown/overexpression and polysome profiling with anti-MRPS15 IP in stressed human cardiomyocytes","pmids":["38542224"],"confidence":"High","gaps":["Mechanism by which MRPS15 relocalizes to cytosolic polysomes is undefined","How MRPS15 selects or activates IRES-containing UPR mRNAs molecularly is not resolved","No structural model of an MRPS15-containing cytosolic ribosome"]},{"year":2026,"claim":"The mitochondrial consequences of MRPS15 loss and its transcriptional control were unknown; knockdown/rescue and epistasis placed MRPS15 as a Zhx1-driven effector required for mitochondrial translation, respiration and protein import in cardiac protection.","evidence":"Knockdown/overexpression in cardiomyocytes, membrane potential and respiration assays, hypertensive heart disease mouse model, Zhx1 activator and combined Mrps15/Mrps21 silencing epistasis","pmids":["42162768"],"confidence":"Medium","gaps":["Separable contributions of MRPS15 versus MRPS21 not dissected","No in vitro reconstitution or structural data for the mitoribosomal role","Direct binding of Zhx1 to the MRPS15 promoter not demonstrated within the timeline"]},{"year":2026,"claim":"Whether mitoribosomal translation rate gates OXPHOS assembly was untested; a suppressor mutation in MRPS-15 that slows translation and restores OXPHOS in LONP-1-deficient worms identified translation speed as a modulator of complex biogenesis.","evidence":"Forward genetic suppressor screen in C. elegans lonp-1 mutants with OXPHOS restoration measurements (preprint)","pmids":["41648325"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mechanism linking slowed translation to improved assembly is inferred, not directly shown","Relevance of the suppressor mechanism to human MRPS15 not established"]},{"year":null,"claim":"How a single protein partitions between mitoribosomal and cytosolic-polysome pools, and what governs that switch under stress, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Signals and trafficking controlling cytosolic relocalization are unknown","Whether the cytosolic and mitochondrial functions share a structural basis is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0]}],"complexes":["mitochondrial small ribosomal subunit (mitoribosome)","cytosolic polysome"],"partners":["MRPS21","ZHX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P82914","full_name":"Small ribosomal subunit protein uS15m","aliases":["28S ribosomal protein S15, mitochondrial","MRP-S15","S15mt"],"length_aa":257,"mass_kda":29.8,"function":"","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P82914/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MRPS15","classification":"Not Classified","n_dependent_lines":276,"n_total_lines":1208,"dependency_fraction":0.22847682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM39","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"TMA16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MRPS15","total_profiled":1310},"omim":[{"mim_id":"614918","title":"PENTATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 3; PTCD3","url":"https://www.omim.org/entry/614918"},{"mim_id":"611979","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN S15; MRPS15","url":"https://www.omim.org/entry/611979"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MRPS15"},"hgnc":{"alias_symbol":["FLJ11564","uS15m"],"prev_symbol":[]},"alphafold":{"accession":"P82914","domains":[{"cath_id":"1.10.287.10","chopping":"75-192","consensus_level":"high","plddt":94.8479,"start":75,"end":192},{"cath_id":"1.20.5","chopping":"201-231","consensus_level":"medium","plddt":97.7261,"start":201,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P82914","model_url":"https://alphafold.ebi.ac.uk/files/AF-P82914-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P82914-F1-predicted_aligned_error_v6.png","plddt_mean":78.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRPS15","jax_strain_url":"https://www.jax.org/strain/search?query=MRPS15"},"sequence":{"accession":"P82914","fasta_url":"https://rest.uniprot.org/uniprotkb/P82914.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P82914/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P82914"}},"corpus_meta":[{"pmid":"23172368","id":"PMC_23172368","title":"Mitochondria \"fuel\" breast cancer metabolism: fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23172368","citation_count":149,"is_preprint":false},{"pmid":"26808329","id":"PMC_26808329","title":"Evaluation of Suitable Internal Control Genes for RT-qPCR in Yak Mammary Tissue during the Lactation Cycle.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26808329","citation_count":18,"is_preprint":false},{"pmid":"38542224","id":"PMC_38542224","title":"Mitochondrial Ribosomal Protein MRPS15 Is a Component of Cytosolic Ribosomes and Regulates Translation in Stressed Cardiomyocytes.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38542224","citation_count":4,"is_preprint":false},{"pmid":"39595553","id":"PMC_39595553","title":"Identifying Hub Genes and Metabolic Pathways in Collagen VI-Related Dystrophies: A Roadmap to Therapeutic Intervention.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39595553","citation_count":1,"is_preprint":false},{"pmid":"40097569","id":"PMC_40097569","title":"Unraveling the intricate molecular landscape and potential biomarkers in lung adenocarcinoma through integrative epigenomic and transcriptomic profiling.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40097569","citation_count":1,"is_preprint":false},{"pmid":"42162768","id":"PMC_42162768","title":"Mrps15/Mrps21 induced by Zhx1 protects mice from hypertensive heart disease by restoring mitochondrial translation.","date":"2026","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42162768","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":"41648325","id":"PMC_41648325","title":"LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41648325","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6718,"output_tokens":1096,"usd":0.018297,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7684,"output_tokens":1974,"usd":0.043885,"stage2_stop_reason":"end_turn"},"total_usd":0.062182,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"MRPS15 is found as a component of cytosolic ribosomes (polysomes) in stressed human cardiomyocytes, not only in mitochondrial ribosomes. Under ER stress induced by tunicamycin, MRPS15 levels in cytosolic polysomes increase dramatically. Its interaction with cytosolic ribosomal proteins was confirmed by proximity ligation assay and immunoprecipitation. Knockdown or overexpression of MRPS15 demonstrated its role as an activator of IRES-dependent translation. Polysome profiling after anti-MRPS15 immunoprecipitation showed that 'MRPS15 ribosomes' are specialized in translating mRNAs involved in the unfolded protein response.\",\n      \"method\": \"Mass spectrometry of translating ribosome composition, proximity ligation assay, immunoprecipitation, knockdown/overexpression functional assays, polysome profiling with anti-MRPS15 immunoprecipitation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (MS, PLA, Co-IP, polysome profiling, KD/OE) in a single focused study establishing a novel cytosolic ribosomal role\",\n      \"pmids\": [\"38542224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of Mrps15 (together with Mrps21) in cardiomyocytes inhibits mitochondrial translation, leading to depolarization of mitochondrial membrane potential, impaired mitochondrial respiration, reduced membrane translocation of nuclear-encoded mitochondrial proteins, and mitochondrial ROS production associated with reduced mitochondrial glutaredoxin-2. Overexpression of Mrps15/Mrps21 restores cardiac function in hypertensive heart disease mice. The transcription factor Zhx1 promotes transcription of Mrps15/Mrps21; combined silencing of Mrps15/Mrps21 compromised the protective effect of Zhx1, placing Mrps15 downstream of Zhx1 in this pathway.\",\n      \"method\": \"Knockdown and overexpression in cardiomyocytes, mitochondrial membrane potential assay, mitochondrial respiration assay, mouse HHD model (L-NAME gavage), Zhx1 activator treatment, epistasis by combined Mrps15/Mrps21 silencing\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and genetic epistasis in a single lab study, but no in vitro reconstitution or structural data\",\n      \"pmids\": [\"42162768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In C. elegans, a point mutation in MRPS-15 (a mitoribosomal small subunit protein) acts as a suppressor of LONP-1 deficiency, restoring mitochondrial function and development. This suppressor mutation is proposed to enhance oxidative phosphorylation complex assembly by slowing mitochondrial translation, placing MRPS-15 as a functional component of the mitoribosome whose activity modulates OXPHOS complex assembly downstream of LONP-1.\",\n      \"method\": \"Forward genetic suppressor screen in C. elegans lonp-1 mutants, identification of suppressor mutations in mitoribosomal protein genes, measurement of oxidative phosphorylation restoration\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis via forward suppressor screen in a model organism, single study, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41648325\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MRPS15 (uS15m) is a mitochondrial ribosomal small subunit protein required for mitochondrial translation and OXPHOS complex assembly; under cellular stress, it additionally localizes to cytosolic polysomes where it activates IRES-dependent translation of unfolded protein response mRNAs, and its mitochondrial function is transcriptionally regulated by the zinc-finger protein Zhx1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MRPS15 (uS15m) is a small-subunit mitoribosomal protein required for mitochondrial translation and the downstream assembly of oxidative phosphorylation complexes [#1, #2]. Loss of MRPS15 (with MRPS21) in cardiomyocytes inhibits mitochondrial translation, depolarizes the mitochondrial membrane potential, impairs respiration, reduces import of nuclear-encoded mitochondrial proteins, and triggers mitochondrial ROS associated with loss of glutaredoxin-2; its transcription is driven by the zinc-finger factor Zhx1, and MRPS15/MRPS21 act downstream of Zhx1 to confer cardioprotection in hypertensive heart disease [#1]. In C. elegans, a point mutation in the MRPS-15 ortholog suppresses LONP-1 deficiency by slowing mitochondrial translation and restoring OXPHOS complex assembly, identifying mitoribosomal translation rate as a tunable determinant of complex biogenesis [#2]. Beyond its canonical mitoribosomal role, MRPS15 is recruited to cytosolic polysomes during ER stress, where it interacts with cytosolic ribosomal proteins and activates IRES-dependent translation of unfolded protein response mRNAs, defining a stress-induced extra-mitochondrial function [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether MRPS15 functions exclusively within mitoribosomes was unknown; this work established a stress-induced cytosolic role in selective translation, expanding the protein's functional repertoire beyond mitochondria.\",\n      \"evidence\": \"Mass spectrometry of translating ribosomes, proximity ligation assay, Co-IP, knockdown/overexpression and polysome profiling with anti-MRPS15 IP in stressed human cardiomyocytes\",\n      \"pmids\": [\"38542224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which MRPS15 relocalizes to cytosolic polysomes is undefined\",\n        \"How MRPS15 selects or activates IRES-containing UPR mRNAs molecularly is not resolved\",\n        \"No structural model of an MRPS15-containing cytosolic ribosome\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The mitochondrial consequences of MRPS15 loss and its transcriptional control were unknown; knockdown/rescue and epistasis placed MRPS15 as a Zhx1-driven effector required for mitochondrial translation, respiration and protein import in cardiac protection.\",\n      \"evidence\": \"Knockdown/overexpression in cardiomyocytes, membrane potential and respiration assays, hypertensive heart disease mouse model, Zhx1 activator and combined Mrps15/Mrps21 silencing epistasis\",\n      \"pmids\": [\"42162768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Separable contributions of MRPS15 versus MRPS21 not dissected\",\n        \"No in vitro reconstitution or structural data for the mitoribosomal role\",\n        \"Direct binding of Zhx1 to the MRPS15 promoter not demonstrated within the timeline\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Whether mitoribosomal translation rate gates OXPHOS assembly was untested; a suppressor mutation in MRPS-15 that slows translation and restores OXPHOS in LONP-1-deficient worms identified translation speed as a modulator of complex biogenesis.\",\n      \"evidence\": \"Forward genetic suppressor screen in C. elegans lonp-1 mutants with OXPHOS restoration measurements (preprint)\",\n      \"pmids\": [\"41648325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Mechanism linking slowed translation to improved assembly is inferred, not directly shown\",\n        \"Relevance of the suppressor mechanism to human MRPS15 not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single protein partitions between mitoribosomal and cytosolic-polysome pools, and what governs that switch under stress, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Signals and trafficking controlling cytosolic relocalization are unknown\",\n        \"Whether the cytosolic and mitochondrial functions share a structural basis is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"mitochondrial small ribosomal subunit (mitoribosome)\", \"cytosolic polysome\"],\n    \"partners\": [\"MRPS21\", \"ZHX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}