{"gene":"UQCRFS1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2012,"finding":"LYRM7/MZM1L functions as a chaperone for UQCRFS1 (Rieske iron-sulfur protein) in the mitochondrial matrix, binding to UQCRFS1 and stabilizing it prior to its translocation and insertion into the late Complex III dimeric intermediate within the mitochondrial inner membrane.","method":"Co-immunoprecipitation, blue-native PAGE, siRNA knockdown, functional complementation in human cell lines","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, knockdown phenotype with defined molecular consequence (failure of UQCRFS1 insertion into CIII intermediate), replicated using multiple cell-line models","pmids":["23168492"],"is_preprint":false},{"year":2017,"finding":"TTC19 binds to the fully assembled Complex III dimer after UQCRFS1 incorporation and is required for the rapid removal of N-terminal processing peptides generated from in situ maturation of UQCRFS1; when TTC19 is absent, these UQCRFS1 fragments accumulate within Complex III, causing structural and functional impairment.","method":"Ttc19 knockout mouse model, blue-native PAGE, mass spectrometry, human cell lines with TTC19 loss-of-function, Complex III activity assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse, human cell lines, MS identification of UQCRFS1 fragments, enzymatic activity), two independent model systems","pmids":["28673544"],"is_preprint":false},{"year":2019,"finding":"Bi-allelic loss-of-function variants in UQCRFS1 cause reduced UQCRFS1 protein abundance, impaired mitochondrial import of UQCRFS1, defective Complex III assembly, and decreased cellular respiration; lentiviral overexpression of wild-type UQCRFS1 in patient-derived fibroblasts restored mitochondrial function, confirming UQCRFS1 as the causal gene.","method":"Patient-derived fibroblast studies, BN-PAGE, oxygen consumption assays, lentiviral complementation, western blotting","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined cellular phenotypes plus complementation rescue, multiple orthogonal assays in patient-derived cells","pmids":["31883641"],"is_preprint":false},{"year":1995,"finding":"The human UQCRFS1 gene encoding the Rieske Fe-S protein was mapped by FISH to chromosome band 19q12; genomic structure including exon-intron junctions was determined from a chromosome 19-specific cosmid library.","method":"Fluorescent in situ hybridization (FISH), cosmid library screening, direct sequencing of exon/intron junctions","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct experimental localization of gene locus, single lab, two orthogonal methods (hybrid cell panel + FISH)","pmids":["7721092"],"is_preprint":false},{"year":2015,"finding":"Intragenic suppressor mutations in the conserved six-amino-acid tether region of C. elegans ISP-1 (Rieske iron-sulfur protein) suppress all pleiotropic phenotypes of the partial loss-of-function isp-1(qm150) allele, including slow development, reduced pharyngeal pumping, lifespan extension, and activated mitochondrial UPR; analogous mutations in yeast Rip1 show conserved structure-function relationships, supporting a 'spring-loaded' model for ISP tether function in electron transfer gating.","method":"C. elegans intragenic suppressor screen, mitochondrial oxidative phosphorylation measurements, CO2 production assays, yeast Rip1 mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple suppressor mutations in a defined domain, multiple phenotypic readouts, cross-species (worm + yeast) validation, multiple orthogonal methods","pmids":["26504246"],"is_preprint":false},{"year":2016,"finding":"Mitochondrial disease-related mutations at the cytochrome b–ISP head domain (ISP-HD) interface (G167P and G332D in Rhodobacter capsulatus, corresponding to G290D in human) shift the equilibrium position of ISP-HD away from the quinol oxidation (Qo) site, leading to enhanced reactive oxygen species production via a 'semireverse' electron transfer mechanism.","method":"Site-directed mutagenesis in Rhodobacter capsulatus, EPR spectroscopy, enzymatic activity assays, electron transfer rate measurements","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bacterial model for human disease mutations, mutagenesis + spectroscopy + activity assays, single lab","pmids":["27032290"],"is_preprint":false},{"year":2025,"finding":"Bcs1 AAA-ATPase transports folded UQCRFS1 (ISP) across the inner mitochondrial membrane; single-molecule HS-AFM analysis revealed that ISP binds exclusively to the matrix cavity of apo-conformation AAA-domains of Bcs1, all Bcs1 subunits act in a conformationally coupled concerted mechanism, and ISP-Bcs1 binding duration outlasts the apo-conformation lifetime during ATP turnover to ensure efficient transport.","method":"High-speed atomic force microscopy (HS-AFM) single-molecule imaging, AMP-PNP/ADP/ATP nucleotide titration experiments","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — single-molecule structural and kinetic data with functional validation, but single lab and single paper","pmids":["41183768"],"is_preprint":false},{"year":2025,"finding":"SP-2509 (N'-(1-phenylethylidene)-benzohydrazide) destabilizes UQCRFS1 protein as detected by cellular thermal shift assay coupled to mass spectrometry (CETSA-MS), likely by impairing iron-sulfur cofactor binding; this compound broadly destabilizes cellular Fe-S proteins.","method":"CETSA-MS (cellular thermal shift assay coupled to mass spectrometry), chemical and genetic validation of LSD1-independence","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, single lab, CETSA-MS is an indirect stability assay without direct Fe-S cluster reconstitution","pmids":["bio_10.1101_2025.06.20.660795"],"is_preprint":true},{"year":2025,"finding":"siRNA knockdown of UQCRFS1 in human ductus arteriosus smooth muscle cells (DASMC) did not impair mitochondrial respiration or electron transport chain activity, and did not affect O2-induced changes in intracellular calcium or cell shortening, unlike knockdown of NDUFS2 (negative result for oxygen-sensing role).","method":"siRNA knockdown, calcium imaging, cell shortening assays, micropolarimetry, ETC activity assays in human DASMC","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab; finding is a well-controlled negative result for an oxygen-sensor role of UQCRFS1 in this specific cell type","pmids":["bio_10.1101_2025.07.08.663799"],"is_preprint":true},{"year":2025,"finding":"UQCRFS1 knockdown dampened proliferative and migratory capacity of triple-negative breast cancer (TNBC) cells in vitro and reduced tumor growth in vivo, demonstrating a functional role in TNBC cell biology.","method":"siRNA knockdown, proliferation assays, migration assays, in vivo xenograft tumor growth","journal":"Experimental hematology & oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic pathway placement beyond OXPHOS/tumor growth phenotype","pmids":["40524231"],"is_preprint":false}],"current_model":"UQCRFS1 encodes the Rieske iron-sulfur protein (ISP), a catalytic subunit of mitochondrial respiratory Complex III (cytochrome bc1), which undergoes chaperone-assisted (LYRM7/MZM1L) stabilization in the matrix before being translocated across the inner mitochondrial membrane by the AAA-ATPase Bcs1 in its folded state and inserted into the late CIII dimeric intermediate; within the assembled CIII dimer, its N-terminal processing peptides are rapidly removed by TTC19, and its head-domain movement between the quinol oxidation (Qo) site and cytochrome c1 gates electron transfer and reactive oxygen species production, with disease-causing mutations perturbing this motion."},"narrative":{"mechanistic_narrative":"UQCRFS1 encodes the Rieske iron-sulfur protein, a catalytic subunit of mitochondrial respiratory Complex III whose biogenesis, maturation, and conformational dynamics are tightly orchestrated [PMID:23168492, PMID:31883641]. Prior to membrane insertion, the matrix chaperone LYRM7/MZM1L binds and stabilizes UQCRFS1, holding it competent for incorporation into the late Complex III dimeric assembly intermediate [PMID:23168492], while the AAA-ATPase Bcs1 transports the folded protein across the inner membrane through a conformationally coupled concerted mechanism in which UQCRFS1 engages only the apo-state matrix cavity of Bcs1 [PMID:41183768]. After incorporation, TTC19 docks onto the assembled dimer and clears the N-terminal processing fragments generated during in situ UQCRFS1 maturation, a step required to avoid fragment accumulation and structural impairment of the complex [PMID:28673544]. Within assembled Complex III, the conserved tether of the Rieske head domain gates electron transfer between the quinol oxidation (Qo) site and cytochrome c1, and mutations in this tether or at the cytochrome b–head-domain interface shift its equilibrium position, altering electron transfer and promoting reactive oxygen species production [PMID:26504246, PMID:27032290]. Bi-allelic loss-of-function variants in UQCRFS1 reduce protein abundance, impair mitochondrial import, and disrupt Complex III assembly and cellular respiration, establishing UQCRFS1 as the causal gene for a mitochondrial Complex III deficiency [PMID:31883641].","teleology":[{"year":1995,"claim":"Establishing the genomic identity and locus of the human Rieske Fe-S protein gene provided the foundation for subsequent disease and assembly studies.","evidence":"FISH mapping and cosmid library sequencing of exon-intron structure","pmids":["7721092"],"confidence":"Medium","gaps":["Does not address protein function or assembly","No expression or localization data"]},{"year":2012,"claim":"It was unknown how UQCRFS1 is maintained in a soluble, insertion-competent state before joining Complex III; identifying LYRM7/MZM1L as a dedicated matrix chaperone defined the pre-insertion stabilization step.","evidence":"Co-IP, blue-native PAGE, siRNA knockdown and complementation in human cell lines","pmids":["23168492"],"confidence":"High","gaps":["Does not resolve how UQCRFS1 is handed off to the import machinery","Structural basis of the chaperone-substrate interaction not defined"]},{"year":2015,"claim":"Whether the Rieske head-domain tether is functionally critical for electron transfer gating was unresolved; intragenic suppressors in the conserved tether established a 'spring-loaded' model linking tether mechanics to mitochondrial phenotypes.","evidence":"C. elegans intragenic suppressor screen with OXPHOS readouts plus yeast Rip1 mutagenesis","pmids":["26504246"],"confidence":"High","gaps":["Direct demonstration in human protein not shown","Quantitative link between tether motion and electron transfer rate not measured"]},{"year":2016,"claim":"It was unclear how disease-associated head-domain mutations cause pathology; mapping mutations at the cytochrome b–ISP head-domain interface showed they shift the head-domain equilibrium away from the Qo site and enhance ROS via semireverse electron transfer.","evidence":"Site-directed mutagenesis in Rhodobacter capsulatus, EPR spectroscopy, electron transfer assays","pmids":["27032290"],"confidence":"Medium","gaps":["Bacterial surrogate for human mutations","ROS measured in vitro, not in patient cells"]},{"year":2017,"claim":"The fate of UQCRFS1 N-terminal processing peptides after incorporation was unknown; TTC19 was shown to bind the assembled dimer and remove these fragments, preventing their accumulation and structural impairment.","evidence":"Ttc19 knockout mouse, human LOF cell lines, mass spectrometry of fragments, Complex III activity assays","pmids":["28673544"],"confidence":"High","gaps":["Mechanism by which fragments are degraded after release not defined","Protease responsible for initial in situ cleavage not identified here"]},{"year":2019,"claim":"Whether UQCRFS1 variants cause human mitochondrial disease was untested; bi-allelic LOF variants with complementation rescue confirmed UQCRFS1 as causal for Complex III deficiency.","evidence":"Patient-derived fibroblasts, BN-PAGE, oxygen consumption, lentiviral rescue","pmids":["31883641"],"confidence":"High","gaps":["Genotype-phenotype correlation across patients not established","Tissue-specific consequences not addressed"]},{"year":2025,"claim":"The molecular mechanism of folded-protein transport across the inner membrane was unresolved; HS-AFM revealed Bcs1 binds folded UQCRFS1 exclusively in its apo conformation through a concerted, conformationally coupled cycle.","evidence":"Single-molecule HS-AFM with nucleotide titration","pmids":["41183768"],"confidence":"Medium","gaps":["Single lab, single study","Energetics of full translocation across the membrane not quantified"]},{"year":2025,"claim":"The breadth of UQCRFS1's cellular roles beyond OXPHOS was explored; knockdown studies showed a requirement in TNBC proliferation and tumor growth but no role in ductus arteriosus oxygen sensing.","evidence":"siRNA knockdown with proliferation/migration/xenograft assays; calcium and ETC assays in DASMC (preprint)","pmids":["40524231","bio_10.1101_2025.07.08.663799"],"confidence":"Low","gaps":["TNBC role lacks mechanistic pathway placement beyond OXPHOS phenotype","Negative oxygen-sensing result limited to one cell type and unreplicated"]},{"year":null,"claim":"How UQCRFS1 stability and Fe-S cofactor loading can be pharmacologically modulated, and whether this is exploitable, remains open.","evidence":"Not yet established in peer-reviewed work","pmids":[],"confidence":"Low","gaps":["SP-2509 destabilization shown only by indirect CETSA-MS in a preprint without Fe-S reconstitution","No direct structural evidence for compound-cofactor interaction"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]}],"complexes":["Complex III (cytochrome bc1)"],"partners":["LYRM7","TTC19","BCS1L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P47985","full_name":"Cytochrome b-c1 complex subunit Rieske, mitochondrial","aliases":["Complex III subunit 5","Cytochrome b-c1 complex subunit 5","Rieske iron-sulfur protein","RISP","Rieske protein UQCRFS1","Ubiquinol-cytochrome c reductase iron-sulfur subunit"],"length_aa":274,"mass_kda":29.7,"function":"Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation (PubMed:31883641). The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c. The Rieske protein is a catalytic core subunit containing a [2Fe-2S] iron-sulfur cluster. It cycles between 2 conformational states during catalysis to transfer electrons from the quinol bound in the Q(0) site in cytochrome b to cytochrome c1 (By similarity). Incorporation of UQCRFS1 is the penultimate step in complex III assembly (PubMed:28673544) Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII). UQCRFS1 undergoes proteolytic processing once it is incorporated in the complex III dimer. One of the fragments, called subunit 9, corresponds to its mitochondrial targeting sequence (MTS). The proteolytic processing is necessary for the correct insertion of UQCRFS1 in the complex III dimer, but the persistence of UQCRFS1-derived fragments may prevent newly imported UQCRFS1 to be processed and assembled into complex III and is detrimental for the complex III structure and function","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P47985/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UQCRFS1","classification":"Common Essential","n_dependent_lines":965,"n_total_lines":1208,"dependency_fraction":0.7988410596026491},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM39","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UQCRFS1","total_profiled":1310},"omim":[{"mim_id":"618775","title":"MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 10; MC3DN10","url":"https://www.omim.org/entry/618775"},{"mim_id":"615831","title":"LYR MOTIF-CONTAINING PROTEIN 7; LYRM7","url":"https://www.omim.org/entry/615831"},{"mim_id":"613814","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 19; TTC19","url":"https://www.omim.org/entry/613814"},{"mim_id":"603647","title":"BCS1 UBIQUINOL-CYTOCHROME C REDUCTASE COMPLEX CHAPERONE; BCS1L","url":"https://www.omim.org/entry/603647"},{"mim_id":"191329","title":"UBIQUINOL-CYTOCHROME c REDUCTASE CORE PROTEIN II; UQCRC2","url":"https://www.omim.org/entry/191329"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":216.9},{"tissue":"tongue","ntpm":267.1}],"url":"https://www.proteinatlas.org/search/UQCRFS1"},"hgnc":{"alias_symbol":["ISP","RIS1","RIP1","UQCR5","RISP"],"prev_symbol":[]},"alphafold":{"accession":"P47985","domains":[{"cath_id":"1.20.5.270","chopping":"85-142","consensus_level":"medium","plddt":95.5376,"start":85,"end":142},{"cath_id":"2.102.10.10","chopping":"150-274","consensus_level":"high","plddt":94.2354,"start":150,"end":274}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47985","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47985-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47985-F1-predicted_aligned_error_v6.png","plddt_mean":80.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UQCRFS1","jax_strain_url":"https://www.jax.org/strain/search?query=UQCRFS1"},"sequence":{"accession":"P47985","fasta_url":"https://rest.uniprot.org/uniprotkb/P47985.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47985/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47985"}},"corpus_meta":[{"pmid":"7794249","id":"PMC_7794249","title":"Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin.","date":"1995","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7794249","citation_count":442,"is_preprint":false},{"pmid":"21931710","id":"PMC_21931710","title":"Microbiological and molecular assessment of bacteriophage ISP for the control of Staphylococcus aureus.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21931710","citation_count":93,"is_preprint":false},{"pmid":"20498075","id":"PMC_20498075","title":"Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20498075","citation_count":87,"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":"28673544","id":"PMC_28673544","title":"TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28673544","citation_count":69,"is_preprint":false},{"pmid":"28392283","id":"PMC_28392283","title":"Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans.","date":"2017","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28392283","citation_count":66,"is_preprint":false},{"pmid":"24107417","id":"PMC_24107417","title":"TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants.","date":"2013","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/24107417","citation_count":42,"is_preprint":false},{"pmid":"31883641","id":"PMC_31883641","title":"Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31883641","citation_count":40,"is_preprint":false},{"pmid":"18261823","id":"PMC_18261823","title":"RISP: a web-based server for prediction of RNA-binding sites in proteins.","date":"2008","source":"Computer methods and programs in biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/18261823","citation_count":36,"is_preprint":false},{"pmid":"9141696","id":"PMC_9141696","title":"The signal peptidase II (Isp) gene of Bacillus subtilis.","date":"1997","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9141696","citation_count":35,"is_preprint":false},{"pmid":"11122537","id":"PMC_11122537","title":"Alteration in sphingolipid metabolism: bioassays for fumonisin- and ISP-I-like activity in tissues, cells and other matrices.","date":"1999","source":"Natural toxins","url":"https://pubmed.ncbi.nlm.nih.gov/11122537","citation_count":31,"is_preprint":false},{"pmid":"28624424","id":"PMC_28624424","title":"Fusaric acid (FA) protects heart failure induced by isoproterenol (ISP) in mice through fibrosis prevention via TGF-β1/SMADs and PI3K/AKT signaling pathways.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28624424","citation_count":31,"is_preprint":false},{"pmid":"15047214","id":"PMC_15047214","title":"Ubiquinol cytochrome c reductase (UQCRFS1) gene amplification in primary breast cancer core biopsy samples.","date":"2004","source":"Gynecologic 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immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8698478","citation_count":27,"is_preprint":false},{"pmid":"20827171","id":"PMC_20827171","title":"Control of HIV replication in astrocytes by a family of highly conserved host proteins with a common Rev-interacting domain (Risp).","date":"2010","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20827171","citation_count":26,"is_preprint":false},{"pmid":"7980560","id":"PMC_7980560","title":"Substitution of the ISP alpha subunit of biphenyl dioxygenase from Pseudomonas results in a modification of the enzyme activity.","date":"1994","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7980560","citation_count":26,"is_preprint":false},{"pmid":"15820214","id":"PMC_15820214","title":"The requirement for the hydrophobic motif phosphorylation of Ypk1 in yeast differs depending on the downstream events, including endocytosis, cell growth, and resistance to a sphingolipid 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blue-native PAGE, siRNA knockdown, functional complementation in human cell lines\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated, knockdown phenotype with defined molecular consequence (failure of UQCRFS1 insertion into CIII intermediate), replicated using multiple cell-line models\",\n      \"pmids\": [\"23168492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TTC19 binds to the fully assembled Complex III dimer after UQCRFS1 incorporation and is required for the rapid removal of N-terminal processing peptides generated from in situ maturation of UQCRFS1; when TTC19 is absent, these UQCRFS1 fragments accumulate within Complex III, causing structural and functional impairment.\",\n      \"method\": \"Ttc19 knockout mouse model, blue-native PAGE, mass spectrometry, human cell lines with TTC19 loss-of-function, Complex III activity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mouse, human cell lines, MS identification of UQCRFS1 fragments, enzymatic activity), two independent model systems\",\n      \"pmids\": [\"28673544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Bi-allelic loss-of-function variants in UQCRFS1 cause reduced UQCRFS1 protein abundance, impaired mitochondrial import of UQCRFS1, defective Complex III assembly, and decreased cellular respiration; lentiviral overexpression of wild-type UQCRFS1 in patient-derived fibroblasts restored mitochondrial function, confirming UQCRFS1 as the causal gene.\",\n      \"method\": \"Patient-derived fibroblast studies, BN-PAGE, oxygen consumption assays, lentiviral complementation, western blotting\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined cellular phenotypes plus complementation rescue, multiple orthogonal assays in patient-derived cells\",\n      \"pmids\": [\"31883641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human UQCRFS1 gene encoding the Rieske Fe-S protein was mapped by FISH to chromosome band 19q12; genomic structure including exon-intron junctions was determined from a chromosome 19-specific cosmid library.\",\n      \"method\": \"Fluorescent in situ hybridization (FISH), cosmid library screening, direct sequencing of exon/intron junctions\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental localization of gene locus, single lab, two orthogonal methods (hybrid cell panel + FISH)\",\n      \"pmids\": [\"7721092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Intragenic suppressor mutations in the conserved six-amino-acid tether region of C. elegans ISP-1 (Rieske iron-sulfur protein) suppress all pleiotropic phenotypes of the partial loss-of-function isp-1(qm150) allele, including slow development, reduced pharyngeal pumping, lifespan extension, and activated mitochondrial UPR; analogous mutations in yeast Rip1 show conserved structure-function relationships, supporting a 'spring-loaded' model for ISP tether function in electron transfer gating.\",\n      \"method\": \"C. elegans intragenic suppressor screen, mitochondrial oxidative phosphorylation measurements, CO2 production assays, yeast Rip1 mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple suppressor mutations in a defined domain, multiple phenotypic readouts, cross-species (worm + yeast) validation, multiple orthogonal methods\",\n      \"pmids\": [\"26504246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mitochondrial disease-related mutations at the cytochrome b–ISP head domain (ISP-HD) interface (G167P and G332D in Rhodobacter capsulatus, corresponding to G290D in human) shift the equilibrium position of ISP-HD away from the quinol oxidation (Qo) site, leading to enhanced reactive oxygen species production via a 'semireverse' electron transfer mechanism.\",\n      \"method\": \"Site-directed mutagenesis in Rhodobacter capsulatus, EPR spectroscopy, enzymatic activity assays, electron transfer rate measurements\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bacterial model for human disease mutations, mutagenesis + spectroscopy + activity assays, single lab\",\n      \"pmids\": [\"27032290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Bcs1 AAA-ATPase transports folded UQCRFS1 (ISP) across the inner mitochondrial membrane; single-molecule HS-AFM analysis revealed that ISP binds exclusively to the matrix cavity of apo-conformation AAA-domains of Bcs1, all Bcs1 subunits act in a conformationally coupled concerted mechanism, and ISP-Bcs1 binding duration outlasts the apo-conformation lifetime during ATP turnover to ensure efficient transport.\",\n      \"method\": \"High-speed atomic force microscopy (HS-AFM) single-molecule imaging, AMP-PNP/ADP/ATP nucleotide titration experiments\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single-molecule structural and kinetic data with functional validation, but single lab and single paper\",\n      \"pmids\": [\"41183768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SP-2509 (N'-(1-phenylethylidene)-benzohydrazide) destabilizes UQCRFS1 protein as detected by cellular thermal shift assay coupled to mass spectrometry (CETSA-MS), likely by impairing iron-sulfur cofactor binding; this compound broadly destabilizes cellular Fe-S proteins.\",\n      \"method\": \"CETSA-MS (cellular thermal shift assay coupled to mass spectrometry), chemical and genetic validation of LSD1-independence\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, single lab, CETSA-MS is an indirect stability assay without direct Fe-S cluster reconstitution\",\n      \"pmids\": [\"bio_10.1101_2025.06.20.660795\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"siRNA knockdown of UQCRFS1 in human ductus arteriosus smooth muscle cells (DASMC) did not impair mitochondrial respiration or electron transport chain activity, and did not affect O2-induced changes in intracellular calcium or cell shortening, unlike knockdown of NDUFS2 (negative result for oxygen-sensing role).\",\n      \"method\": \"siRNA knockdown, calcium imaging, cell shortening assays, micropolarimetry, ETC activity assays in human DASMC\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab; finding is a well-controlled negative result for an oxygen-sensor role of UQCRFS1 in this specific cell type\",\n      \"pmids\": [\"bio_10.1101_2025.07.08.663799\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UQCRFS1 knockdown dampened proliferative and migratory capacity of triple-negative breast cancer (TNBC) cells in vitro and reduced tumor growth in vivo, demonstrating a functional role in TNBC cell biology.\",\n      \"method\": \"siRNA knockdown, proliferation assays, migration assays, in vivo xenograft tumor growth\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic pathway placement beyond OXPHOS/tumor growth phenotype\",\n      \"pmids\": [\"40524231\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UQCRFS1 encodes the Rieske iron-sulfur protein (ISP), a catalytic subunit of mitochondrial respiratory Complex III (cytochrome bc1), which undergoes chaperone-assisted (LYRM7/MZM1L) stabilization in the matrix before being translocated across the inner mitochondrial membrane by the AAA-ATPase Bcs1 in its folded state and inserted into the late CIII dimeric intermediate; within the assembled CIII dimer, its N-terminal processing peptides are rapidly removed by TTC19, and its head-domain movement between the quinol oxidation (Qo) site and cytochrome c1 gates electron transfer and reactive oxygen species production, with disease-causing mutations perturbing this motion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UQCRFS1 encodes the Rieske iron-sulfur protein, a catalytic subunit of mitochondrial respiratory Complex III whose biogenesis, maturation, and conformational dynamics are tightly orchestrated [#0, #2]. Prior to membrane insertion, the matrix chaperone LYRM7/MZM1L binds and stabilizes UQCRFS1, holding it competent for incorporation into the late Complex III dimeric assembly intermediate [#0], while the AAA-ATPase Bcs1 transports the folded protein across the inner membrane through a conformationally coupled concerted mechanism in which UQCRFS1 engages only the apo-state matrix cavity of Bcs1 [#6]. After incorporation, TTC19 docks onto the assembled dimer and clears the N-terminal processing fragments generated during in situ UQCRFS1 maturation, a step required to avoid fragment accumulation and structural impairment of the complex [#1]. Within assembled Complex III, the conserved tether of the Rieske head domain gates electron transfer between the quinol oxidation (Qo) site and cytochrome c1, and mutations in this tether or at the cytochrome b\\u2013head-domain interface shift its equilibrium position, altering electron transfer and promoting reactive oxygen species production [#4, #5]. Bi-allelic loss-of-function variants in UQCRFS1 reduce protein abundance, impair mitochondrial import, and disrupt Complex III assembly and cellular respiration, establishing UQCRFS1 as the causal gene for a mitochondrial Complex III deficiency [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the genomic identity and locus of the human Rieske Fe-S protein gene provided the foundation for subsequent disease and assembly studies.\",\n      \"evidence\": \"FISH mapping and cosmid library sequencing of exon-intron structure\",\n      \"pmids\": [\"7721092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address protein function or assembly\", \"No expression or localization data\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"It was unknown how UQCRFS1 is maintained in a soluble, insertion-competent state before joining Complex III; identifying LYRM7/MZM1L as a dedicated matrix chaperone defined the pre-insertion stabilization step.\",\n      \"evidence\": \"Co-IP, blue-native PAGE, siRNA knockdown and complementation in human cell lines\",\n      \"pmids\": [\"23168492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how UQCRFS1 is handed off to the import machinery\", \"Structural basis of the chaperone-substrate interaction not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether the Rieske head-domain tether is functionally critical for electron transfer gating was unresolved; intragenic suppressors in the conserved tether established a 'spring-loaded' model linking tether mechanics to mitochondrial phenotypes.\",\n      \"evidence\": \"C. elegans intragenic suppressor screen with OXPHOS readouts plus yeast Rip1 mutagenesis\",\n      \"pmids\": [\"26504246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration in human protein not shown\", \"Quantitative link between tether motion and electron transfer rate not measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"It was unclear how disease-associated head-domain mutations cause pathology; mapping mutations at the cytochrome b\\u2013ISP head-domain interface showed they shift the head-domain equilibrium away from the Qo site and enhance ROS via semireverse electron transfer.\",\n      \"evidence\": \"Site-directed mutagenesis in Rhodobacter capsulatus, EPR spectroscopy, electron transfer assays\",\n      \"pmids\": [\"27032290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bacterial surrogate for human mutations\", \"ROS measured in vitro, not in patient cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The fate of UQCRFS1 N-terminal processing peptides after incorporation was unknown; TTC19 was shown to bind the assembled dimer and remove these fragments, preventing their accumulation and structural impairment.\",\n      \"evidence\": \"Ttc19 knockout mouse, human LOF cell lines, mass spectrometry of fragments, Complex III activity assays\",\n      \"pmids\": [\"28673544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which fragments are degraded after release not defined\", \"Protease responsible for initial in situ cleavage not identified here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether UQCRFS1 variants cause human mitochondrial disease was untested; bi-allelic LOF variants with complementation rescue confirmed UQCRFS1 as causal for Complex III deficiency.\",\n      \"evidence\": \"Patient-derived fibroblasts, BN-PAGE, oxygen consumption, lentiviral rescue\",\n      \"pmids\": [\"31883641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation across patients not established\", \"Tissue-specific consequences not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The molecular mechanism of folded-protein transport across the inner membrane was unresolved; HS-AFM revealed Bcs1 binds folded UQCRFS1 exclusively in its apo conformation through a concerted, conformationally coupled cycle.\",\n      \"evidence\": \"Single-molecule HS-AFM with nucleotide titration\",\n      \"pmids\": [\"41183768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single study\", \"Energetics of full translocation across the membrane not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The breadth of UQCRFS1's cellular roles beyond OXPHOS was explored; knockdown studies showed a requirement in TNBC proliferation and tumor growth but no role in ductus arteriosus oxygen sensing.\",\n      \"evidence\": \"siRNA knockdown with proliferation/migration/xenograft assays; calcium and ETC assays in DASMC (preprint)\",\n      \"pmids\": [\"40524231\", \"bio_10.1101_2025.07.08.663799\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"TNBC role lacks mechanistic pathway placement beyond OXPHOS phenotype\", \"Negative oxygen-sensing result limited to one cell type and unreplicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UQCRFS1 stability and Fe-S cofactor loading can be pharmacologically modulated, and whether this is exploitable, remains open.\",\n      \"evidence\": \"Not yet established in peer-reviewed work\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"SP-2509 destabilization shown only by indirect CETSA-MS in a preprint without Fe-S reconstitution\", \"No direct structural evidence for compound-cofactor interaction\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0009055\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"Complex III (cytochrome bc1)\"],\n    \"partners\": [\"LYRM7\", \"TTC19\", \"BCS1L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}