{"gene":"LYRM7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2012,"finding":"LYRM7/MZM1L functions as a chaperone for the Rieske Fe-S protein (UQCRFS1), binding to UQCRFS1 within the mitochondrial matrix and stabilizing it prior to its translocation and insertion into the late Complex III dimeric intermediate within the mitochondrial inner membrane, thereby acting as a novel assembly factor for the last steps of CIII biogenesis.","method":"Co-immunoprecipitation, cellular fractionation, knockdown/complementation assays, homology to yeast Mzm1","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding and functional characterization in human cells, replicated in yeast model, multiple orthogonal methods across independent labs","pmids":["23168492"],"is_preprint":false},{"year":2013,"finding":"A missense mutation (p.Asp25Asn) in LYRM7 causes impaired maturation/stabilization of the Rieske Fe-S protein and reduced Complex III activity; the equivalent yeast mzm1(D25N) allele recapitulates temperature-sensitive respiratory growth defect and decreased oxygen consumption in mzm1Δ yeast, confirming Asp25 as functionally critical.","method":"Patient mutation analysis, yeast complementation assay, oxygen consumption measurement, Complex III activity assay","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — active-site mutagenesis equivalent validated by functional yeast complementation with multiple biochemical readouts, replicated across human patient and yeast model","pmids":["24014394"],"is_preprint":false},{"year":2015,"finding":"LYRM7/MZM1L is established as a chaperone involved in CIII biogenesis in human cells, with additional data further defining its molecular role in UQCRFS1 stabilization prior to insertion into the Complex III assembly intermediate.","method":"Biochemical assays, cell-based complementation, review with new experimental data","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation data provided but described as 'additional data' supplementing prior work; single lab, abstract details sparse","pmids":["25914718"],"is_preprint":false},{"year":2015,"finding":"LYRM7 is classified among LYR motif proteins that function as novel assembly factors for OXPHOS core complexes; structural and biochemical analyses of related LYRMs (LYRM3, LYRM6) show these proteins reside at specific positions within Complex I and can anchor acyl-carrier protein (ACPM), providing structural context for the LYRM superfamily to which LYRM7 belongs.","method":"Comparative analysis of EM and X-ray structures of Complex I; protein-protein interaction screens; genetic analyses","journal":"Biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — structural/biochemical insights are for paralogous LYRMs (LYRM3, LYRM6), not LYRM7 directly; LYRM7's specific assembly factor role inferred by analogy","pmids":["25686363"],"is_preprint":false},{"year":2016,"finding":"Loss of LYRM7 function (via homozygous truncating mutations) causes profound Complex III deficiency in human fibroblasts, as demonstrated by functional complementation with lentiviral LYRM7 re-expression restoring Complex III enzymatic activity.","method":"Lentiviral complementation of patient fibroblasts, spectrophotometric enzymatic assay, exome and Sanger sequencing","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral complementation with enzymatic rescue is a clean loss-of-function/gain-of-function experiment, single lab, two orthogonal methods","pmids":["27151179"],"is_preprint":false},{"year":2016,"finding":"Patients with LYRM7 mutations show decreased Complex III holocomplex in fibroblasts, and functional studies in yeast confirmed pathogenicity of novel LYRM7 mutations; LYRM7 protein is strongly reduced in patient samples.","method":"Blue-native gel electrophoresis, yeast functional complementation, Western blot, Sanger sequencing","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (BN-PAGE, yeast complementation, Western blot) in single study","pmids":["26912632"],"is_preprint":false},{"year":2017,"finding":"Re-expression of LYRM7 in patient fibroblasts (carrying a splice-site deletion) restores the reduced amount of the Rieske Fe-S protein (UQCRFS1), directly linking LYRM7 function to UQCRFS1 stabilization in human cells.","method":"LYRM7 re-expression in patient fibroblasts, Western blot quantification of UQCRFS1","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementation with direct protein-level readout for UQCRFS1, single lab","pmids":["28694194"],"is_preprint":false},{"year":2023,"finding":"TNF-α-induced NF-κB transcriptionally regulates LYRM7 expression; knockdown of LYRM7 in MDA-MB-231 breast cancer cells decreases mitochondrial supercomplex assembly, enhances ROS levels, and increases invasion and migration potential, placing LYRM7 downstream of NF-κB in regulation of mitochondrial function and cancer cell behavior.","method":"TNF-α treatment, NF-κB pathway analysis, siRNA knockdown of LYRM7, supercomplex assembly assay (BN-PAGE), ROS measurement, invasion/migration assays, in vivo Infliximab treatment","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (BN-PAGE, ROS, functional invasion/migration, in vivo), single lab","pmids":["38104742"],"is_preprint":false}],"current_model":"LYRM7/MZM1L is a mitochondrial matrix chaperone that binds and stabilizes the Rieske Fe-S protein (UQCRFS1), facilitating its translocation and insertion into the late Complex III dimeric intermediate within the inner membrane; it is transcriptionally regulated by TNF-α/NF-κB, and its loss causes defective UQCRFS1 maturation, reduced Complex III holocomplex assembly, impaired supercomplex formation, and elevated ROS, leading to mitochondrial respiratory chain deficiency."},"narrative":{"mechanistic_narrative":"LYRM7 (MZM1L) is a mitochondrial matrix chaperone that operates in the final steps of mitochondrial Complex III (CIII) biogenesis by binding and stabilizing the Rieske Fe-S protein UQCRFS1 prior to its translocation and insertion into the late CIII dimeric assembly intermediate of the inner membrane [PMID:23168492]. Re-expression of LYRM7 in patient fibroblasts restores reduced UQCRFS1 levels, directly establishing UQCRFS1 stabilization as its core function in human cells [PMID:28694194]. The conserved residue Asp25 is functionally critical: a p.Asp25Asn substitution impairs UQCRFS1 maturation and reduces CIII activity, a defect recapitulated by the equivalent yeast mzm1 allele [PMID:24014394]. Loss of LYRM7 function through truncating mutations causes profound CIII deficiency with reduced holocomplex, rescuable by LYRM7 re-expression, defining LYRM7 as a cause of mitochondrial CIII-deficiency disease [PMID:27151179, PMID:26912632]. Beyond its assembly role, LYRM7 is a transcriptional target of TNF-α/NF-κB signaling, and its depletion in breast cancer cells reduces respiratory supercomplex assembly, elevates ROS, and promotes invasion and migration [PMID:38104742].","teleology":[{"year":2012,"claim":"Established that LYRM7 is a dedicated chaperone for the Rieske Fe-S protein, answering how UQCRFS1 is stabilized before its membrane insertion during CIII assembly.","evidence":"Co-immunoprecipitation, cellular fractionation, knockdown/complementation in human cells with yeast Mzm1 homology","pmids":["23168492"],"confidence":"High","gaps":["No structure of the LYRM7-UQCRFS1 complex","Mechanism of how LYRM7 hands off UQCRFS1 to the inner membrane intermediate not resolved"]},{"year":2013,"claim":"Identified Asp25 as a functionally critical residue, linking a specific human missense mutation to defective UQCRFS1 maturation and demonstrating disease relevance.","evidence":"Patient mutation analysis with yeast complementation, oxygen consumption and CIII activity assays","pmids":["24014394"],"confidence":"High","gaps":["Structural basis for why Asp25 is required not defined","Whether Asp25 contributes to UQCRFS1 binding specifically unresolved"]},{"year":2015,"claim":"Consolidated LYRM7's chaperone role in human CIII biogenesis and placed it within the broader LYR-motif assembly-factor superfamily.","evidence":"Cell-based complementation and biochemical assays; comparative structural analysis of paralogous LYRMs (LYRM3, LYRM6)","pmids":["25914718","25686363"],"confidence":"Medium","gaps":["Structural data are for paralogs, not LYRM7 directly","Whether LYRM7 anchors acyl-carrier protein like other LYRMs untested"]},{"year":2016,"claim":"Demonstrated that loss-of-function mutations cause CIII deficiency reversible by re-expression, confirming LYRM7 as causal for the disease phenotype and reducing the CIII holocomplex.","evidence":"Lentiviral complementation of patient fibroblasts, spectrophotometric CIII assays, BN-PAGE, yeast complementation, exome/Sanger sequencing","pmids":["27151179","26912632"],"confidence":"Medium","gaps":["Tissue-specific consequences of CIII deficiency not detailed","Genotype-phenotype correlation across mutations incomplete"]},{"year":2017,"claim":"Provided direct human-cell evidence that LYRM7 function determines UQCRFS1 protein levels, confirming the stabilization mechanism at the protein level.","evidence":"LYRM7 re-expression in patient fibroblasts with Western blot quantification of UQCRFS1","pmids":["28694194"],"confidence":"Medium","gaps":["Does not distinguish stabilization from facilitated synthesis/folding kinetics","Single patient/cell-line context"]},{"year":2023,"claim":"Extended LYRM7 biology beyond assembly to signaling-regulated mitochondrial control, placing it downstream of TNF-α/NF-κB and linking its loss to supercomplex disruption and a pro-invasive cancer phenotype.","evidence":"TNF-α treatment, NF-κB analysis, siRNA knockdown in MDA-MB-231 cells, BN-PAGE supercomplex assay, ROS measurement, invasion/migration assays, in vivo Infliximab treatment","pmids":["38104742"],"confidence":"Medium","gaps":["Direct NF-κB binding to the LYRM7 promoter not mapped","Causal chain from supercomplex loss to invasion via ROS not fully dissected","Single cancer cell-line model"]},{"year":null,"claim":"How LYRM7 structurally engages UQCRFS1 and mechanistically coordinates its release into the membrane-embedded CIII intermediate remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental structure of LYRM7 or the LYRM7-UQCRFS1 complex","Handoff mechanism to the late CIII dimeric intermediate undefined","Regulation of LYRM7 across tissues beyond NF-κB unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["UQCRFS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5U5X0","full_name":"Complex III assembly factor LYRM7","aliases":["LYR motif-containing protein 7"],"length_aa":104,"mass_kda":12.0,"function":"Assembly factor required for Rieske Fe-S protein UQCRFS1 incorporation into the cytochrome b-c1 (CIII) complex. Functions as a chaperone, binding to this subunit within the mitochondrial matrix and stabilizing it prior to its translocation and insertion into the late CIII dimeric intermediate within the mitochondrial inner membrane","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q5U5X0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LYRM7","classification":"Not Classified","n_dependent_lines":34,"n_total_lines":1208,"dependency_fraction":0.028145695364238412},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LYRM7","total_profiled":1310},"omim":[{"mim_id":"615838","title":"MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 8; MC3DN8","url":"https://www.omim.org/entry/615838"},{"mim_id":"615831","title":"LYR MOTIF-CONTAINING PROTEIN 7; LYRM7","url":"https://www.omim.org/entry/615831"},{"mim_id":"191327","title":"UBIQUINOL-CYTOCHROME c REDUCTASE, RIESKE IRON-SULFUR; UQCRFS1","url":"https://www.omim.org/entry/191327"},{"mim_id":"124000","title":"MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1; MC3DN1","url":"https://www.omim.org/entry/124000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"tongue","ntpm":31.5}],"url":"https://www.proteinatlas.org/search/LYRM7"},"hgnc":{"alias_symbol":["FLJ20796","MZM1L"],"prev_symbol":["C5orf31"]},"alphafold":{"accession":"Q5U5X0","domains":[{"cath_id":"1.20.1270","chopping":"2-88","consensus_level":"high","plddt":94.5362,"start":2,"end":88}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5U5X0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5U5X0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5U5X0-F1-predicted_aligned_error_v6.png","plddt_mean":91.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LYRM7","jax_strain_url":"https://www.jax.org/strain/search?query=LYRM7"},"sequence":{"accession":"Q5U5X0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5U5X0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5U5X0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5U5X0"}},"corpus_meta":[{"pmid":"25914718","id":"PMC_25914718","title":"Nuclear gene mutations as the cause of mitochondrial complex III deficiency.","date":"2015","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25914718","citation_count":112,"is_preprint":false},{"pmid":"23168492","id":"PMC_23168492","title":"LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of mitochondrial Complex III assembly in human cells.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23168492","citation_count":72,"is_preprint":false},{"pmid":"25686363","id":"PMC_25686363","title":"Eukaryotic LYR Proteins Interact with Mitochondrial Protein Complexes.","date":"2015","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/25686363","citation_count":67,"is_preprint":false},{"pmid":"24014394","id":"PMC_24014394","title":"A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.","date":"2013","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/24014394","citation_count":64,"is_preprint":false},{"pmid":"26912632","id":"PMC_26912632","title":"LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance.","date":"2016","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26912632","citation_count":55,"is_preprint":false},{"pmid":"28804536","id":"PMC_28804536","title":"Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.","date":"2017","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/28804536","citation_count":34,"is_preprint":false},{"pmid":"25899669","id":"PMC_25899669","title":"Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25899669","citation_count":29,"is_preprint":false},{"pmid":"38044432","id":"PMC_38044432","title":"Decoding the mitochondrial connection: development and validation of biomarkers for classifying and treating systemic lupus erythematosus through bioinformatics and machine learning.","date":"2023","source":"BMC rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/38044432","citation_count":28,"is_preprint":false},{"pmid":"30770271","id":"PMC_30770271","title":"Genotypic Spectrum and Natural History of Cavitating Leukoencephalopathies in Childhood.","date":"2019","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30770271","citation_count":28,"is_preprint":false},{"pmid":"27151179","id":"PMC_27151179","title":"Severe respiratory complex III defect prevents liver adaptation to prolonged fasting.","date":"2016","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/27151179","citation_count":26,"is_preprint":false},{"pmid":"28694194","id":"PMC_28694194","title":"LYRM7 - associated complex III deficiency: A clinical, molecular genetic, MR tomographic, and biochemical study.","date":"2017","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/28694194","citation_count":22,"is_preprint":false},{"pmid":"40254778","id":"PMC_40254778","title":"Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.","date":"2025","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/40254778","citation_count":19,"is_preprint":false},{"pmid":"25452764","id":"PMC_25452764","title":"A novel mutation in TTC19 associated with isolated complex III deficiency, cerebellar hypoplasia, and bilateral basal ganglia lesions.","date":"2014","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25452764","citation_count":18,"is_preprint":false},{"pmid":"38104742","id":"PMC_38104742","title":"TNF-α induced NF-κB mediated LYRM7 expression modulates the tumor growth and metastatic ability in breast cancer.","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38104742","citation_count":17,"is_preprint":false},{"pmid":"37698381","id":"PMC_37698381","title":"Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high-intensity interval training.","date":"2023","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/37698381","citation_count":15,"is_preprint":false},{"pmid":"36757047","id":"PMC_36757047","title":"LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes.","date":"2023","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36757047","citation_count":12,"is_preprint":false},{"pmid":"33189022","id":"PMC_33189022","title":"Multifocal cavitating leukodystrophy-A distinct image in mitochondrial LYRM7 mutations.","date":"2020","source":"Multiple sclerosis and related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/33189022","citation_count":9,"is_preprint":false},{"pmid":"39605484","id":"PMC_39605484","title":"Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39605484","citation_count":3,"is_preprint":false},{"pmid":"37669117","id":"PMC_37669117","title":"Invasive Breast Cancer: miR-24-2 Targets Genes Associated with Survival and Sensitizes MDA-MB-231 Cells to Berberine.","date":"2023","source":"Omics : a journal of integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/37669117","citation_count":2,"is_preprint":false},{"pmid":"40317892","id":"PMC_40317892","title":"A Novel Presentation and Variable Phenotypic Spectrum of Homozygous Start-Loss Variant in LYRM7-Associated Mitochondrial Complex III Deficiency.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40317892","citation_count":1,"is_preprint":false},{"pmid":"41045959","id":"PMC_41045959","title":"Sudden bilateral vision loss in a child with LYRM7-related leukoencephalopathy.","date":"2025","source":"Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus","url":"https://pubmed.ncbi.nlm.nih.gov/41045959","citation_count":0,"is_preprint":false},{"pmid":"41686563","id":"PMC_41686563","title":"Decoding lactylation in neuropathic pain: Immune cell infiltration patterns and machine learning-identified candidate biomarkers.","date":"2026","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41686563","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13366,"output_tokens":1942,"usd":0.034614,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8907,"output_tokens":2285,"usd":0.05083,"stage2_stop_reason":"end_turn"},"total_usd":0.085444,"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\": 2012,\n      \"finding\": \"LYRM7/MZM1L functions as a chaperone for the Rieske Fe-S protein (UQCRFS1), binding to UQCRFS1 within the mitochondrial matrix and stabilizing it prior to its translocation and insertion into the late Complex III dimeric intermediate within the mitochondrial inner membrane, thereby acting as a novel assembly factor for the last steps of CIII biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, cellular fractionation, knockdown/complementation assays, homology to yeast Mzm1\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding and functional characterization in human cells, replicated in yeast model, multiple orthogonal methods across independent labs\",\n      \"pmids\": [\"23168492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A missense mutation (p.Asp25Asn) in LYRM7 causes impaired maturation/stabilization of the Rieske Fe-S protein and reduced Complex III activity; the equivalent yeast mzm1(D25N) allele recapitulates temperature-sensitive respiratory growth defect and decreased oxygen consumption in mzm1Δ yeast, confirming Asp25 as functionally critical.\",\n      \"method\": \"Patient mutation analysis, yeast complementation assay, oxygen consumption measurement, Complex III activity assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — active-site mutagenesis equivalent validated by functional yeast complementation with multiple biochemical readouts, replicated across human patient and yeast model\",\n      \"pmids\": [\"24014394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LYRM7/MZM1L is established as a chaperone involved in CIII biogenesis in human cells, with additional data further defining its molecular role in UQCRFS1 stabilization prior to insertion into the Complex III assembly intermediate.\",\n      \"method\": \"Biochemical assays, cell-based complementation, review with new experimental data\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation data provided but described as 'additional data' supplementing prior work; single lab, abstract details sparse\",\n      \"pmids\": [\"25914718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LYRM7 is classified among LYR motif proteins that function as novel assembly factors for OXPHOS core complexes; structural and biochemical analyses of related LYRMs (LYRM3, LYRM6) show these proteins reside at specific positions within Complex I and can anchor acyl-carrier protein (ACPM), providing structural context for the LYRM superfamily to which LYRM7 belongs.\",\n      \"method\": \"Comparative analysis of EM and X-ray structures of Complex I; protein-protein interaction screens; genetic analyses\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — structural/biochemical insights are for paralogous LYRMs (LYRM3, LYRM6), not LYRM7 directly; LYRM7's specific assembly factor role inferred by analogy\",\n      \"pmids\": [\"25686363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of LYRM7 function (via homozygous truncating mutations) causes profound Complex III deficiency in human fibroblasts, as demonstrated by functional complementation with lentiviral LYRM7 re-expression restoring Complex III enzymatic activity.\",\n      \"method\": \"Lentiviral complementation of patient fibroblasts, spectrophotometric enzymatic assay, exome and Sanger sequencing\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral complementation with enzymatic rescue is a clean loss-of-function/gain-of-function experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"27151179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Patients with LYRM7 mutations show decreased Complex III holocomplex in fibroblasts, and functional studies in yeast confirmed pathogenicity of novel LYRM7 mutations; LYRM7 protein is strongly reduced in patient samples.\",\n      \"method\": \"Blue-native gel electrophoresis, yeast functional complementation, Western blot, Sanger sequencing\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (BN-PAGE, yeast complementation, Western blot) in single study\",\n      \"pmids\": [\"26912632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Re-expression of LYRM7 in patient fibroblasts (carrying a splice-site deletion) restores the reduced amount of the Rieske Fe-S protein (UQCRFS1), directly linking LYRM7 function to UQCRFS1 stabilization in human cells.\",\n      \"method\": \"LYRM7 re-expression in patient fibroblasts, Western blot quantification of UQCRFS1\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementation with direct protein-level readout for UQCRFS1, single lab\",\n      \"pmids\": [\"28694194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNF-α-induced NF-κB transcriptionally regulates LYRM7 expression; knockdown of LYRM7 in MDA-MB-231 breast cancer cells decreases mitochondrial supercomplex assembly, enhances ROS levels, and increases invasion and migration potential, placing LYRM7 downstream of NF-κB in regulation of mitochondrial function and cancer cell behavior.\",\n      \"method\": \"TNF-α treatment, NF-κB pathway analysis, siRNA knockdown of LYRM7, supercomplex assembly assay (BN-PAGE), ROS measurement, invasion/migration assays, in vivo Infliximab treatment\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (BN-PAGE, ROS, functional invasion/migration, in vivo), single lab\",\n      \"pmids\": [\"38104742\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LYRM7/MZM1L is a mitochondrial matrix chaperone that binds and stabilizes the Rieske Fe-S protein (UQCRFS1), facilitating its translocation and insertion into the late Complex III dimeric intermediate within the inner membrane; it is transcriptionally regulated by TNF-α/NF-κB, and its loss causes defective UQCRFS1 maturation, reduced Complex III holocomplex assembly, impaired supercomplex formation, and elevated ROS, leading to mitochondrial respiratory chain deficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LYRM7 (MZM1L) is a mitochondrial matrix chaperone that operates in the final steps of mitochondrial Complex III (CIII) biogenesis by binding and stabilizing the Rieske Fe-S protein UQCRFS1 prior to its translocation and insertion into the late CIII dimeric assembly intermediate of the inner membrane [#0]. Re-expression of LYRM7 in patient fibroblasts restores reduced UQCRFS1 levels, directly establishing UQCRFS1 stabilization as its core function in human cells [#6]. The conserved residue Asp25 is functionally critical: a p.Asp25Asn substitution impairs UQCRFS1 maturation and reduces CIII activity, a defect recapitulated by the equivalent yeast mzm1 allele [#1]. Loss of LYRM7 function through truncating mutations causes profound CIII deficiency with reduced holocomplex, rescuable by LYRM7 re-expression, defining LYRM7 as a cause of mitochondrial CIII-deficiency disease [#4, #5]. Beyond its assembly role, LYRM7 is a transcriptional target of TNF-α/NF-κB signaling, and its depletion in breast cancer cells reduces respiratory supercomplex assembly, elevates ROS, and promotes invasion and migration [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that LYRM7 is a dedicated chaperone for the Rieske Fe-S protein, answering how UQCRFS1 is stabilized before its membrane insertion during CIII assembly.\",\n      \"evidence\": \"Co-immunoprecipitation, cellular fractionation, knockdown/complementation in human cells with yeast Mzm1 homology\",\n      \"pmids\": [\"23168492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the LYRM7-UQCRFS1 complex\", \"Mechanism of how LYRM7 hands off UQCRFS1 to the inner membrane intermediate not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified Asp25 as a functionally critical residue, linking a specific human missense mutation to defective UQCRFS1 maturation and demonstrating disease relevance.\",\n      \"evidence\": \"Patient mutation analysis with yeast complementation, oxygen consumption and CIII activity assays\",\n      \"pmids\": [\"24014394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for why Asp25 is required not defined\", \"Whether Asp25 contributes to UQCRFS1 binding specifically unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Consolidated LYRM7's chaperone role in human CIII biogenesis and placed it within the broader LYR-motif assembly-factor superfamily.\",\n      \"evidence\": \"Cell-based complementation and biochemical assays; comparative structural analysis of paralogous LYRMs (LYRM3, LYRM6)\",\n      \"pmids\": [\"25914718\", \"25686363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural data are for paralogs, not LYRM7 directly\", \"Whether LYRM7 anchors acyl-carrier protein like other LYRMs untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that loss-of-function mutations cause CIII deficiency reversible by re-expression, confirming LYRM7 as causal for the disease phenotype and reducing the CIII holocomplex.\",\n      \"evidence\": \"Lentiviral complementation of patient fibroblasts, spectrophotometric CIII assays, BN-PAGE, yeast complementation, exome/Sanger sequencing\",\n      \"pmids\": [\"27151179\", \"26912632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific consequences of CIII deficiency not detailed\", \"Genotype-phenotype correlation across mutations incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided direct human-cell evidence that LYRM7 function determines UQCRFS1 protein levels, confirming the stabilization mechanism at the protein level.\",\n      \"evidence\": \"LYRM7 re-expression in patient fibroblasts with Western blot quantification of UQCRFS1\",\n      \"pmids\": [\"28694194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not distinguish stabilization from facilitated synthesis/folding kinetics\", \"Single patient/cell-line context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended LYRM7 biology beyond assembly to signaling-regulated mitochondrial control, placing it downstream of TNF-α/NF-κB and linking its loss to supercomplex disruption and a pro-invasive cancer phenotype.\",\n      \"evidence\": \"TNF-α treatment, NF-κB analysis, siRNA knockdown in MDA-MB-231 cells, BN-PAGE supercomplex assay, ROS measurement, invasion/migration assays, in vivo Infliximab treatment\",\n      \"pmids\": [\"38104742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NF-κB binding to the LYRM7 promoter not mapped\", \"Causal chain from supercomplex loss to invasion via ROS not fully dissected\", \"Single cancer cell-line model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LYRM7 structurally engages UQCRFS1 and mechanistically coordinates its release into the membrane-embedded CIII intermediate remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of LYRM7 or the LYRM7-UQCRFS1 complex\", \"Handoff mechanism to the late CIII dimeric intermediate undefined\", \"Regulation of LYRM7 across tissues beyond NF-κB unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1852241\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"UQCRFS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}