{"gene":"MICOS13","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2015,"finding":"QIL1 (MICOS13/C19orf70) was identified as a novel subunit of the human MICOS complex via systematic proteomic analysis. Its depletion causes MICOS disassembly, resulting in accumulation of a MIC60-MIC19-MIC25 sub-complex and degradation of MIC10, MIC26, and MIC27, indicating QIL1 is required for the stable assembly of the full MICOS complex.","method":"Quantitative proteomics (AP-MS), siRNA knockdown in human cells and Drosophila, co-immunoprecipitation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, quantitative proteomics, in vivo Drosophila validation, multiple orthogonal methods in a single rigorous study","pmids":["25997101"],"is_preprint":false},{"year":2015,"finding":"Upon QIL1 depletion, overexpressed MIC10 fails to significantly restore its interaction with other MICOS subunits and SAMM50, demonstrating that QIL1 is required for MIC10 integration into the MICOS complex rather than merely for MIC10 stability.","method":"Co-immunoprecipitation following MIC10 overexpression in QIL1-depleted cells","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, Co-IP with overexpression rescue experiment, clear functional readout","pmids":["25997101"],"is_preprint":false},{"year":2016,"finding":"MIC13 is an inner mitochondrial membrane protein that physically interacts with MIC60 (a central MICOS subunit). CRISPR/Cas9 knockout of MIC13 causes complete loss of crista junctions without disrupting respiratory chain supercomplex assembly or mitochondrial network morphology, establishing MIC13 as strictly required for crista junction formation.","method":"CRISPR/Cas9 knockout, complexome profiling, co-immunoprecipitation, electron microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with clear CJ phenotype, complexome profiling, physical interaction confirmed, multiple orthogonal methods","pmids":["27479602"],"is_preprint":false},{"year":2016,"finding":"MIC13 is required for the assembly of MIC10, MIC26, and MIC27 into the MICOS complex, but is dispensable for formation of the MIC60/MIC19/MIC25 sub-complex, defining the hierarchical dependency within MICOS assembly.","method":"CRISPR/Cas9 knockout, complexome profiling, immunoblotting","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with complexome profiling, replicated across studies","pmids":["27479602"],"is_preprint":false},{"year":2016,"finding":"In the yeast MICOS system, Mic12 (ortholog of MIC13) is required for coupling the two MICOS sub-complexes (Mic60-Mic19 module and Mic10-Mic12-Mic26-Mic27 membrane-sculpting module), while Mic27 promotes stability of Mic10 oligomers. Deletion of Mic12 disrupts MICOS complex formation.","method":"Yeast genetics (deletion mutants), co-immunoprecipitation, BN-PAGE","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast ortholog, multiple co-IP and BN-PAGE experiments establishing bridging role, consistent with mammalian data","pmids":["26968360"],"is_preprint":false},{"year":2016,"finding":"QIL1 null alleles in human patients cause MICOS disassembly in fibroblasts, with absence of MIC10 protein while MIC60 remains present. Re-expression of QIL1 rescues cristae defects and promotes re-accumulation of MICOS subunits, confirming QIL1's direct role in MICOS assembly in human disease.","method":"Patient fibroblast analysis, lentiviral rescue expression, immunoblotting, electron microscopy","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient KO fibroblasts with rescue experiment, replicated across independent patient families","pmids":["27623147"],"is_preprint":false},{"year":2016,"finding":"QIL1/MIC13 deficiency in patient fibroblasts causes complete loss of MIC10 and QIL1/MIC13 proteins while MIC60 remains, linking MICOS disassembly specifically to the MIC10-containing sub-complex and resulting in aberrant cristae morphology and mitochondrial respiratory dysfunction.","method":"Patient fibroblast immunoblotting, electron microscopy, respiratory chain activity assays","journal":"European journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent patient cohort replicating MICOS disassembly mechanism, multiple methods","pmids":["27485409"],"is_preprint":false},{"year":2018,"finding":"A splice-site mutation in C19orf70/QIL1 causes loss of the MIC10-MIC26-MIC27-QIL1 sub-complex while leaving a partial MICOS complex, resulting in loss of cristae junctions, aberrant cristae structure, and severely impaired OXPHOS activity in liver and muscle tissue.","method":"Patient tissue analysis, immunoblotting, BN-PAGE, electron microscopy, respiratory chain enzyme assays","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, patient tissue, multiple biochemical methods, no rescue experiment reported","pmids":["29618761"],"is_preprint":false},{"year":2021,"finding":"Systematic deletion mutagenesis of MIC13 identified that a GxxxG motif in the N-terminal transmembrane segment is essential for membrane insertion of MIC13 and stability of the MIC10-subcomplex, while an internal WN motif is essential for MIC13 stability, formation of the MIC10-subcomplex, and interaction with both MIC10- and MIC60-subcomplexes, thereby bridging the two MICOS modules.","method":"20-amino-acid deletion variants expressed in MIC13-KO cells, BN-PAGE, co-immunoprecipitation, electron microscopy, immunoblotting","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with multiple orthogonal methods (BN-PAGE, Co-IP, EM), defines specific functional residues, single lab","pmids":["34271005"],"is_preprint":false},{"year":2024,"finding":"Stomatin-like protein 2 (SLP2) was identified as a key interaction partner of MIC13 and functions as an interaction hub for MICOS subunits, stabilizing MIC26 by protecting it from YME1L-mediated degradation. YME1L depletion in MIC13-KO cells stabilizes the MIC10-subcomplex and restores MIC60-MIC10 interaction and crista junction formation, indicating MIC13's primary role is in MIC10-subcomplex stabilization rather than directly bridging MIC60 and MIC10.","method":"Co-immunoprecipitation, genetic KO (MIC13 KO, SLP2 KO, double KO, YME1L depletion), BN-PAGE, STED super-resolution microscopy, electron microscopy","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO combinations, Co-IP, super-resolution microscopy and EM, functional rescue experiment, mechanistically refines prior model","pmids":["39720525"],"is_preprint":false},{"year":2020,"finding":"Loss of MICOS13 protein in patient fibroblasts results in fewer cristae structures and mitochondrial respiratory chain complex deficiencies; stable lentiviral re-expression of wild-type MICOS13 cDNA rescued respiratory chain complex deficiencies, confirming the causal role of MICOS13 in maintaining mitochondrial respiratory function.","method":"Patient fibroblast analysis, lentiviral rescue, electron microscopy, respiratory chain complex activity assays","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblasts with lentiviral rescue, single lab, multiple functional readouts","pmids":["32749073"],"is_preprint":false},{"year":2025,"finding":"Proximity biotinylation (APEX2) using MIC13 as bait in MIC13-KO mammalian cells identified 119 common and 50 unique proximity interactors (MINDNet), including OXPHOS proteins, protein translocases of the inner and outer membrane, mitochondrial ribosomal proteins, and solute carrier family transporters, revealing MIC13's nanoscale neighborhood within mitochondria.","method":"APEX2 proximity biotinylation in KO cells, mass spectrometry, STED super-resolution nanoscopy, DAB-EM","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics in KO cells with STED/EM validation, preprint, single lab","pmids":["bio_10.1101_2025.05.20.655052"],"is_preprint":true}],"current_model":"MICOS13 (QIL1/MIC13) is an inner mitochondrial membrane protein with a GxxxG transmembrane motif required for membrane insertion and an internal WN motif required for protein stability; it acts as a critical bridge between the MIC60-subcomplex and the MIC10-subcomplex of the MICOS complex by stabilizing the MIC10-containing subcomplex (in part by protecting it from YME1L-mediated degradation, facilitated by interaction with SLP2), and is strictly required for crista junction formation, normal cristae morphology, mitochondrial respiration, and mitochondrial DNA maintenance, with loss-of-function mutations causing fatal infantile mitochondrial hepato-encephalopathy in humans."},"narrative":{"mechanistic_narrative":"MICOS13 (QIL1/MIC13/C19orf70) is an inner mitochondrial membrane subunit of the MICOS complex that is strictly required for crista junction formation and normal cristae architecture [PMID:25997101, PMID:27479602]. It governs the hierarchical assembly of MICOS by coupling the two structural modules: it is dispensable for the MIC60/MIC19/MIC25 subcomplex but is required for incorporation and stability of the MIC10-containing membrane-sculpting subcomplex (MIC10/MIC26/MIC27), such that its loss collapses MICOS into a residual MIC60 subcomplex with loss of MIC10 [PMID:25997101, PMID:27479602]. The yeast ortholog Mic12 plays the equivalent bridging role between the two subcomplexes [PMID:26968360]. Membrane insertion of MIC13 depends on an N-terminal GxxxG transmembrane motif, while an internal WN motif is required for its own stability and for its interaction with both the MIC10- and MIC60-subcomplexes [PMID:34271005]. Its primary action is stabilization of the MIC10-subcomplex: MIC13 interacts with stomatin-like protein 2 (SLP2) to protect MIC26 and the MIC10-subcomplex from YME1L-mediated degradation, and depleting YME1L in MIC13-knockout cells restores the MIC10-subcomplex, MIC60-MIC10 interaction, and crista junctions [PMID:39720525]. Through this assembly role MICOS13 is required for mitochondrial respiratory chain function, with re-expression rescuing respiratory deficiencies in patient cells [PMID:32749073]. Loss-of-function mutations in human MICOS13 cause a fatal infantile mitochondrial hepato-encephalopathy with MICOS disassembly, cristae defects, and impaired OXPHOS [PMID:27623147, PMID:27485409, PMID:29618761].","teleology":[{"year":2015,"claim":"Established that an uncharacterized protein is an obligate subunit of the human MICOS complex, answering whether MICOS assembly requires factors beyond the known MIC60/MIC10 cores.","evidence":"Quantitative AP-MS, siRNA knockdown in human cells and Drosophila, and reciprocal Co-IP","pmids":["25997101"],"confidence":"High","gaps":["Did not resolve whether MIC10 loss reflected failed integration versus instability","No structural basis for how QIL1 couples subcomplexes"]},{"year":2015,"claim":"Distinguished assembly from stability by showing QIL1 is needed to integrate MIC10 into MICOS rather than merely to maintain MIC10 levels.","evidence":"Co-IP after MIC10 overexpression in QIL1-depleted human cells","pmids":["25997101"],"confidence":"Medium","gaps":["Overexpression rescue is indirect; molecular contact points untested","Did not address SAMM50/MIB integration mechanism"]},{"year":2016,"claim":"Defined MIC13 as strictly required for crista junction formation and mapped the hierarchical MICOS assembly dependency in human cells.","evidence":"CRISPR/Cas9 knockout with complexome profiling, Co-IP, and electron microscopy","pmids":["27479602"],"confidence":"High","gaps":["Did not identify the residues mediating bridging","Crista junction loss without supercomplex disruption left functional consequence partly open"]},{"year":2016,"claim":"Confirmed the bridging role is evolutionarily conserved by showing the yeast ortholog Mic12 couples the Mic60 and Mic10 modules.","evidence":"Yeast deletion genetics, Co-IP, and BN-PAGE","pmids":["26968360"],"confidence":"High","gaps":["Yeast subunit composition differs from mammals","No structural model of the coupling interface"]},{"year":2016,"claim":"Linked MICOS13 to human disease and confirmed causality by showing patient null alleles disassemble MICOS and that re-expression rescues cristae defects.","evidence":"Patient fibroblast analysis with lentiviral rescue, immunoblotting, and EM across independent families","pmids":["27623147","27485409"],"confidence":"High","gaps":["Tissue-specific basis of hepato-encephalopathy not explained","Mechanism connecting cristae loss to bioenergetic failure not dissected"]},{"year":2018,"claim":"Extended the disease phenotype to liver and muscle tissue, showing a splice-site mutation selectively eliminates the MIC10-MIC26-MIC27-QIL1 subcomplex with severe OXPHOS impairment.","evidence":"Patient tissue immunoblotting, BN-PAGE, EM, and respiratory chain enzyme assays","pmids":["29618761"],"confidence":"Medium","gaps":["No rescue experiment reported","Single patient/lab"]},{"year":2020,"claim":"Confirmed the causal role of MICOS13 in maintaining respiratory chain function through genetic complementation in patient cells.","evidence":"Patient fibroblasts with lentiviral wild-type re-expression, EM, and respiratory chain complex activity assays","pmids":["32749073"],"confidence":"Medium","gaps":["Single lab","Did not separate cristae structural defect from direct respiratory effects"]},{"year":2021,"claim":"Mapped the functional architecture of MIC13 to specific motifs, defining a GxxxG motif for membrane insertion and a WN motif for stability and dual-subcomplex interaction.","evidence":"Systematic deletion-variant expression in MIC13-KO cells with BN-PAGE, Co-IP, and EM","pmids":["34271005"],"confidence":"High","gaps":["No atomic structure of motif-mediated contacts","Single lab"]},{"year":2024,"claim":"Refined the mechanistic model from direct bridging to subcomplex stabilization by showing MIC13 acts via SLP2 to protect the MIC10-subcomplex from YME1L proteolysis.","evidence":"Multiple genetic KO combinations (MIC13, SLP2, YME1L), Co-IP, BN-PAGE, STED nanoscopy, and EM with functional rescue","pmids":["39720525"],"confidence":"High","gaps":["Precise SLP2-MIC13 interaction interface unresolved","How stabilization translates into crista junction geometry not fully defined"]},{"year":2025,"claim":"Defined the nanoscale molecular neighborhood of MIC13, placing it adjacent to OXPHOS, translocase, ribosomal, and solute carrier machinery.","evidence":"APEX2 proximity biotinylation in KO cells with mass spectrometry, STED nanoscopy, and DAB-EM (preprint)","pmids":["bio_10.1101_2025.05.20.655052"],"confidence":"Medium","gaps":["Proximity does not establish direct interaction","Preprint, single lab, awaits peer review"]},{"year":null,"claim":"How MIC13-dependent stabilization of the MIC10-subcomplex is mechanically converted into crista junction formation, and the structural basis of its motif-mediated contacts, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of MIC13 within MICOS","Mechanistic link between cristae morphology and tissue-specific disease severity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,4,8,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,8]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,3,8]}],"complexes":["MICOS complex"],"partners":["MIC60","MIC10","MIC26","MIC27","SLP2","YME1L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5XKP0","full_name":"MICOS complex subunit MIC13","aliases":["Protein P117"],"length_aa":118,"mass_kda":13.1,"function":"Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane (PubMed:25997101, PubMed:27623147, PubMed:32567732). Constituent of mature MICOS complex, it is required for the formation of cristae junction (CJ) and maintenance of cristae morphology (PubMed:25997101, PubMed:27623147, PubMed:32567732). Required for the incorporation of MICOS10/MIC10 into the MICOS complex (PubMed:25997101, PubMed:27623147)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q5XKP0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MICOS13","classification":"Not Classified","n_dependent_lines":212,"n_total_lines":1208,"dependency_fraction":0.17549668874172186},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MICOS13","total_profiled":1310},"omim":[{"mim_id":"618329","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 37; COXPD37","url":"https://www.omim.org/entry/618329"},{"mim_id":"616658","title":"MITOCHONDRIAL CONTACT SITE AND CRISTAE ORGANIZING SYSTEM, 13-KD SUBUNIT; MICOS13","url":"https://www.omim.org/entry/616658"},{"mim_id":"609060","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 1; COXPD1","url":"https://www.omim.org/entry/609060"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MICOS13"},"hgnc":{"alias_symbol":["QIL1","P117","MIC13","MIC12"],"prev_symbol":["C19orf70"]},"alphafold":{"accession":"Q5XKP0","domains":[{"cath_id":"1.20.5","chopping":"1-31","consensus_level":"medium","plddt":87.7542,"start":1,"end":31},{"cath_id":"1.20.5","chopping":"33-68","consensus_level":"medium","plddt":82.6686,"start":33,"end":68},{"cath_id":"1.20.5","chopping":"80-118","consensus_level":"medium","plddt":92.6013,"start":80,"end":118}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XKP0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XKP0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XKP0-F1-predicted_aligned_error_v6.png","plddt_mean":86.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MICOS13","jax_strain_url":"https://www.jax.org/strain/search?query=MICOS13"},"sequence":{"accession":"Q5XKP0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5XKP0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5XKP0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XKP0"}},"corpus_meta":[{"pmid":"25997101","id":"PMC_25997101","title":"QIL1 is a novel mitochondrial protein required for MICOS complex stability and cristae morphology.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25997101","citation_count":148,"is_preprint":false},{"pmid":"27479602","id":"PMC_27479602","title":"Mic13 Is Essential for Formation of Crista Junctions in Mammalian Cells.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27479602","citation_count":69,"is_preprint":false},{"pmid":"27623147","id":"PMC_27623147","title":"QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27623147","citation_count":55,"is_preprint":false},{"pmid":"27485409","id":"PMC_27485409","title":"Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit.","date":"2016","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/27485409","citation_count":54,"is_preprint":false},{"pmid":"26968360","id":"PMC_26968360","title":"Distinct Roles of Mic12 and Mic27 in the Mitochondrial Contact Site and Cristae Organizing System.","date":"2016","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26968360","citation_count":51,"is_preprint":false},{"pmid":"29618761","id":"PMC_29618761","title":"QIL1-dependent assembly of MICOS complex-lethal mutation in C19ORF70 resulting in liver disease and severe neurological retardation.","date":"2018","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29618761","citation_count":38,"is_preprint":false},{"pmid":"19214710","id":"PMC_19214710","title":"Novel protein RGPR-p117: its role as the regucalcin gene transcription factor.","date":"2009","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19214710","citation_count":28,"is_preprint":false},{"pmid":"32749073","id":"PMC_32749073","title":"A novel homozygous variant in MICOS13/QIL1 causes hepato-encephalopathy with mitochondrial DNA depletion syndrome.","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32749073","citation_count":20,"is_preprint":false},{"pmid":"16676356","id":"PMC_16676356","title":"Overexpression of RGPR-p117 enhances regucalcin gene promoter activity in cloned normal rat kidney proximal tubular epithelial cells: involvement of TTGGC motif.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16676356","citation_count":15,"is_preprint":false},{"pmid":"16211248","id":"PMC_16211248","title":"Nuclear localization of a novel protein, RGPR-p117, in cloned normal rat kidney proximal tubular epithelial cells.","date":"2005","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16211248","citation_count":13,"is_preprint":false},{"pmid":"34271005","id":"PMC_34271005","title":"Conserved GxxxG and WN motifs of MIC13 are essential for bridging two MICOS subcomplexes.","date":"2021","source":"Biochimica et biophysica acta. Biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/34271005","citation_count":12,"is_preprint":false},{"pmid":"30795627","id":"PMC_30795627","title":"A QIL1 Variant Associated with Ventricular Arrhythmias and Sudden Cardiac Death in the Juvenile Rhodesian Ridgeback Dog.","date":"2019","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/30795627","citation_count":11,"is_preprint":false},{"pmid":"28413634","id":"PMC_28413634","title":"Involvement of regucalcin gene promoter region-related protein-p117, a transcription factor, in human obesity.","date":"2017","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/28413634","citation_count":6,"is_preprint":false},{"pmid":"3979119","id":"PMC_3979119","title":"Cell surface differentiation antigen of human muscle encoded by a gene (MIC12) on chromosome 15.","date":"1985","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3979119","citation_count":6,"is_preprint":false},{"pmid":"39720525","id":"PMC_39720525","title":"SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39720525","citation_count":5,"is_preprint":false},{"pmid":"37886246","id":"PMC_37886246","title":"In Silico Vaccine Design and Expression of the Multi-Component Protein Candidate against the Toxoplasma gondii Parasite from MIC13, GRA1, and SAG1 Antigens.","date":"2023","source":"Iranian journal of parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/37886246","citation_count":5,"is_preprint":false},{"pmid":"17549392","id":"PMC_17549392","title":"Overexpression of RGPR-p117 induces the decrease in protein and DNA contents in cloned normal rat kidney proximal tubular epithelial NRK52E cells.","date":"2007","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17549392","citation_count":5,"is_preprint":false},{"pmid":"40546389","id":"PMC_40546389","title":"Design and immunological evaluation of a multi-epitope vaccine candidate against Toxoplasma gondii incorporating MIC13, GRA1, and SAG1 antigens in BALB/c mice.","date":"2025","source":"Food and waterborne parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/40546389","citation_count":4,"is_preprint":false},{"pmid":"35835253","id":"PMC_35835253","title":"The overexpressed transcription factor RGPR-p117 suppresses the proliferation of normal rat kidney proximal tubular epithelial NRK-52E cells: Involvement of diverse signaling pathways.","date":"2022","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35835253","citation_count":3,"is_preprint":false},{"pmid":"39780531","id":"PMC_39780531","title":"Overexpression of RGPR-p117 reveals anticancer effects by regulating multiple signaling pathways in bone metastatic human breast cancer MDA-MB-231 cells.","date":"2025","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/39780531","citation_count":3,"is_preprint":false},{"pmid":"40907915","id":"PMC_40907915","title":"The advanced role of the transcription factor RGPR-p117 in cell regulation: Its involvement in transcription, cell growth, and lipid metabolism.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40907915","citation_count":1,"is_preprint":false},{"pmid":"41049564","id":"PMC_41049564","title":"MIC13 of Toxoplasma gondii: Potential Gene for Vaccine Candidate-An In Silico Approach.","date":"2025","source":"Journal of parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/41049564","citation_count":0,"is_preprint":false},{"pmid":"41265250","id":"PMC_41265250","title":"CRISPR/Cas9-mediated editing of MIC13 in human induced pluripotent stem cells: A model for mitochondrial hepato-encephalopathy.","date":"2025","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41265250","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.20.655052","title":"MINDNet: Proximity interactome of the MICOS complex revealing a multifaceted network orchestrating mitochondrial biogenesis","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.20.655052","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14184,"output_tokens":2947,"usd":0.043379,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10316,"output_tokens":3119,"usd":0.064778,"stage2_stop_reason":"end_turn"},"total_usd":0.108157,"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\": 2015,\n      \"finding\": \"QIL1 (MICOS13/C19orf70) was identified as a novel subunit of the human MICOS complex via systematic proteomic analysis. Its depletion causes MICOS disassembly, resulting in accumulation of a MIC60-MIC19-MIC25 sub-complex and degradation of MIC10, MIC26, and MIC27, indicating QIL1 is required for the stable assembly of the full MICOS complex.\",\n      \"method\": \"Quantitative proteomics (AP-MS), siRNA knockdown in human cells and Drosophila, co-immunoprecipitation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, quantitative proteomics, in vivo Drosophila validation, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"25997101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Upon QIL1 depletion, overexpressed MIC10 fails to significantly restore its interaction with other MICOS subunits and SAMM50, demonstrating that QIL1 is required for MIC10 integration into the MICOS complex rather than merely for MIC10 stability.\",\n      \"method\": \"Co-immunoprecipitation following MIC10 overexpression in QIL1-depleted cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, Co-IP with overexpression rescue experiment, clear functional readout\",\n      \"pmids\": [\"25997101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIC13 is an inner mitochondrial membrane protein that physically interacts with MIC60 (a central MICOS subunit). CRISPR/Cas9 knockout of MIC13 causes complete loss of crista junctions without disrupting respiratory chain supercomplex assembly or mitochondrial network morphology, establishing MIC13 as strictly required for crista junction formation.\",\n      \"method\": \"CRISPR/Cas9 knockout, complexome profiling, co-immunoprecipitation, electron microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with clear CJ phenotype, complexome profiling, physical interaction confirmed, multiple orthogonal methods\",\n      \"pmids\": [\"27479602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIC13 is required for the assembly of MIC10, MIC26, and MIC27 into the MICOS complex, but is dispensable for formation of the MIC60/MIC19/MIC25 sub-complex, defining the hierarchical dependency within MICOS assembly.\",\n      \"method\": \"CRISPR/Cas9 knockout, complexome profiling, immunoblotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with complexome profiling, replicated across studies\",\n      \"pmids\": [\"27479602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In the yeast MICOS system, Mic12 (ortholog of MIC13) is required for coupling the two MICOS sub-complexes (Mic60-Mic19 module and Mic10-Mic12-Mic26-Mic27 membrane-sculpting module), while Mic27 promotes stability of Mic10 oligomers. Deletion of Mic12 disrupts MICOS complex formation.\",\n      \"method\": \"Yeast genetics (deletion mutants), co-immunoprecipitation, BN-PAGE\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast ortholog, multiple co-IP and BN-PAGE experiments establishing bridging role, consistent with mammalian data\",\n      \"pmids\": [\"26968360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"QIL1 null alleles in human patients cause MICOS disassembly in fibroblasts, with absence of MIC10 protein while MIC60 remains present. Re-expression of QIL1 rescues cristae defects and promotes re-accumulation of MICOS subunits, confirming QIL1's direct role in MICOS assembly in human disease.\",\n      \"method\": \"Patient fibroblast analysis, lentiviral rescue expression, immunoblotting, electron microscopy\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient KO fibroblasts with rescue experiment, replicated across independent patient families\",\n      \"pmids\": [\"27623147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"QIL1/MIC13 deficiency in patient fibroblasts causes complete loss of MIC10 and QIL1/MIC13 proteins while MIC60 remains, linking MICOS disassembly specifically to the MIC10-containing sub-complex and resulting in aberrant cristae morphology and mitochondrial respiratory dysfunction.\",\n      \"method\": \"Patient fibroblast immunoblotting, electron microscopy, respiratory chain activity assays\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent patient cohort replicating MICOS disassembly mechanism, multiple methods\",\n      \"pmids\": [\"27485409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A splice-site mutation in C19orf70/QIL1 causes loss of the MIC10-MIC26-MIC27-QIL1 sub-complex while leaving a partial MICOS complex, resulting in loss of cristae junctions, aberrant cristae structure, and severely impaired OXPHOS activity in liver and muscle tissue.\",\n      \"method\": \"Patient tissue analysis, immunoblotting, BN-PAGE, electron microscopy, respiratory chain enzyme assays\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, patient tissue, multiple biochemical methods, no rescue experiment reported\",\n      \"pmids\": [\"29618761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Systematic deletion mutagenesis of MIC13 identified that a GxxxG motif in the N-terminal transmembrane segment is essential for membrane insertion of MIC13 and stability of the MIC10-subcomplex, while an internal WN motif is essential for MIC13 stability, formation of the MIC10-subcomplex, and interaction with both MIC10- and MIC60-subcomplexes, thereby bridging the two MICOS modules.\",\n      \"method\": \"20-amino-acid deletion variants expressed in MIC13-KO cells, BN-PAGE, co-immunoprecipitation, electron microscopy, immunoblotting\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with multiple orthogonal methods (BN-PAGE, Co-IP, EM), defines specific functional residues, single lab\",\n      \"pmids\": [\"34271005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Stomatin-like protein 2 (SLP2) was identified as a key interaction partner of MIC13 and functions as an interaction hub for MICOS subunits, stabilizing MIC26 by protecting it from YME1L-mediated degradation. YME1L depletion in MIC13-KO cells stabilizes the MIC10-subcomplex and restores MIC60-MIC10 interaction and crista junction formation, indicating MIC13's primary role is in MIC10-subcomplex stabilization rather than directly bridging MIC60 and MIC10.\",\n      \"method\": \"Co-immunoprecipitation, genetic KO (MIC13 KO, SLP2 KO, double KO, YME1L depletion), BN-PAGE, STED super-resolution microscopy, electron microscopy\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO combinations, Co-IP, super-resolution microscopy and EM, functional rescue experiment, mechanistically refines prior model\",\n      \"pmids\": [\"39720525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of MICOS13 protein in patient fibroblasts results in fewer cristae structures and mitochondrial respiratory chain complex deficiencies; stable lentiviral re-expression of wild-type MICOS13 cDNA rescued respiratory chain complex deficiencies, confirming the causal role of MICOS13 in maintaining mitochondrial respiratory function.\",\n      \"method\": \"Patient fibroblast analysis, lentiviral rescue, electron microscopy, respiratory chain complex activity assays\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblasts with lentiviral rescue, single lab, multiple functional readouts\",\n      \"pmids\": [\"32749073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Proximity biotinylation (APEX2) using MIC13 as bait in MIC13-KO mammalian cells identified 119 common and 50 unique proximity interactors (MINDNet), including OXPHOS proteins, protein translocases of the inner and outer membrane, mitochondrial ribosomal proteins, and solute carrier family transporters, revealing MIC13's nanoscale neighborhood within mitochondria.\",\n      \"method\": \"APEX2 proximity biotinylation in KO cells, mass spectrometry, STED super-resolution nanoscopy, DAB-EM\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics in KO cells with STED/EM validation, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.05.20.655052\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MICOS13 (QIL1/MIC13) is an inner mitochondrial membrane protein with a GxxxG transmembrane motif required for membrane insertion and an internal WN motif required for protein stability; it acts as a critical bridge between the MIC60-subcomplex and the MIC10-subcomplex of the MICOS complex by stabilizing the MIC10-containing subcomplex (in part by protecting it from YME1L-mediated degradation, facilitated by interaction with SLP2), and is strictly required for crista junction formation, normal cristae morphology, mitochondrial respiration, and mitochondrial DNA maintenance, with loss-of-function mutations causing fatal infantile mitochondrial hepato-encephalopathy in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MICOS13 (QIL1/MIC13/C19orf70) is an inner mitochondrial membrane subunit of the MICOS complex that is strictly required for crista junction formation and normal cristae architecture [#0, #2]. It governs the hierarchical assembly of MICOS by coupling the two structural modules: it is dispensable for the MIC60/MIC19/MIC25 subcomplex but is required for incorporation and stability of the MIC10-containing membrane-sculpting subcomplex (MIC10/MIC26/MIC27), such that its loss collapses MICOS into a residual MIC60 subcomplex with loss of MIC10 [#0, #1, #3]. The yeast ortholog Mic12 plays the equivalent bridging role between the two subcomplexes [#4]. Membrane insertion of MIC13 depends on an N-terminal GxxxG transmembrane motif, while an internal WN motif is required for its own stability and for its interaction with both the MIC10- and MIC60-subcomplexes [#8]. Its primary action is stabilization of the MIC10-subcomplex: MIC13 interacts with stomatin-like protein 2 (SLP2) to protect MIC26 and the MIC10-subcomplex from YME1L-mediated degradation, and depleting YME1L in MIC13-knockout cells restores the MIC10-subcomplex, MIC60-MIC10 interaction, and crista junctions [#9]. Through this assembly role MICOS13 is required for mitochondrial respiratory chain function, with re-expression rescuing respiratory deficiencies in patient cells [#10]. Loss-of-function mutations in human MICOS13 cause a fatal infantile mitochondrial hepato-encephalopathy with MICOS disassembly, cristae defects, and impaired OXPHOS [#5, #6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that an uncharacterized protein is an obligate subunit of the human MICOS complex, answering whether MICOS assembly requires factors beyond the known MIC60/MIC10 cores.\",\n      \"evidence\": \"Quantitative AP-MS, siRNA knockdown in human cells and Drosophila, and reciprocal Co-IP\",\n      \"pmids\": [\"25997101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether MIC10 loss reflected failed integration versus instability\", \"No structural basis for how QIL1 couples subcomplexes\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Distinguished assembly from stability by showing QIL1 is needed to integrate MIC10 into MICOS rather than merely to maintain MIC10 levels.\",\n      \"evidence\": \"Co-IP after MIC10 overexpression in QIL1-depleted human cells\",\n      \"pmids\": [\"25997101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression rescue is indirect; molecular contact points untested\", \"Did not address SAMM50/MIB integration mechanism\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined MIC13 as strictly required for crista junction formation and mapped the hierarchical MICOS assembly dependency in human cells.\",\n      \"evidence\": \"CRISPR/Cas9 knockout with complexome profiling, Co-IP, and electron microscopy\",\n      \"pmids\": [\"27479602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the residues mediating bridging\", \"Crista junction loss without supercomplex disruption left functional consequence partly open\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed the bridging role is evolutionarily conserved by showing the yeast ortholog Mic12 couples the Mic60 and Mic10 modules.\",\n      \"evidence\": \"Yeast deletion genetics, Co-IP, and BN-PAGE\",\n      \"pmids\": [\"26968360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast subunit composition differs from mammals\", \"No structural model of the coupling interface\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked MICOS13 to human disease and confirmed causality by showing patient null alleles disassemble MICOS and that re-expression rescues cristae defects.\",\n      \"evidence\": \"Patient fibroblast analysis with lentiviral rescue, immunoblotting, and EM across independent families\",\n      \"pmids\": [\"27623147\", \"27485409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific basis of hepato-encephalopathy not explained\", \"Mechanism connecting cristae loss to bioenergetic failure not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the disease phenotype to liver and muscle tissue, showing a splice-site mutation selectively eliminates the MIC10-MIC26-MIC27-QIL1 subcomplex with severe OXPHOS impairment.\",\n      \"evidence\": \"Patient tissue immunoblotting, BN-PAGE, EM, and respiratory chain enzyme assays\",\n      \"pmids\": [\"29618761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiment reported\", \"Single patient/lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed the causal role of MICOS13 in maintaining respiratory chain function through genetic complementation in patient cells.\",\n      \"evidence\": \"Patient fibroblasts with lentiviral wild-type re-expression, EM, and respiratory chain complex activity assays\",\n      \"pmids\": [\"32749073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not separate cristae structural defect from direct respiratory effects\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the functional architecture of MIC13 to specific motifs, defining a GxxxG motif for membrane insertion and a WN motif for stability and dual-subcomplex interaction.\",\n      \"evidence\": \"Systematic deletion-variant expression in MIC13-KO cells with BN-PAGE, Co-IP, and EM\",\n      \"pmids\": [\"34271005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic structure of motif-mediated contacts\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the mechanistic model from direct bridging to subcomplex stabilization by showing MIC13 acts via SLP2 to protect the MIC10-subcomplex from YME1L proteolysis.\",\n      \"evidence\": \"Multiple genetic KO combinations (MIC13, SLP2, YME1L), Co-IP, BN-PAGE, STED nanoscopy, and EM with functional rescue\",\n      \"pmids\": [\"39720525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise SLP2-MIC13 interaction interface unresolved\", \"How stabilization translates into crista junction geometry not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the nanoscale molecular neighborhood of MIC13, placing it adjacent to OXPHOS, translocase, ribosomal, and solute carrier machinery.\",\n      \"evidence\": \"APEX2 proximity biotinylation in KO cells with mass spectrometry, STED nanoscopy, and DAB-EM (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.20.655052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximity does not establish direct interaction\", \"Preprint, single lab, awaits peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MIC13-dependent stabilization of the MIC10-subcomplex is mechanically converted into crista junction formation, and the structural basis of its motif-mediated contacts, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of MIC13 within MICOS\", \"Mechanistic link between cristae morphology and tissue-specific disease severity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 4, 8, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3, 8]}\n    ],\n    \"complexes\": [\"MICOS complex\"],\n    \"partners\": [\"MIC60\", \"MIC10\", \"MIC26\", \"MIC27\", \"SLP2\", \"YME1L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}