{"gene":"MISO1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2010,"finding":"AC3-33 (C3orf33/MISO1) is a secretory protein that inhibits AP-1 transcriptional activity by downregulating phosphorylation of ERK1/2, but not JNK/SAPK or p38 MAPK, thereby suppressing Elk1 and c-Jun transcriptional activity but not c-Fos.","method":"Overexpression in cells, dual-luciferase reporter assay, Western blotting for phospho-ERK1/2, AP-1 DNA-binding assay","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, overexpression approach with multiple readouts (reporter assay, DNA-binding, phospho-Western), no rescue or mutagenesis","pmids":["20680465"],"is_preprint":false},{"year":2010,"finding":"AC3-33 (C3orf33/MISO1) protein is localized in the cytoplasm, consistent with its role as a secretory protein with a signal sequence, and inhibits AP-1 transcriptional activity when overexpressed.","method":"Subcellular localization by fluorescence microscopy; recombinant protein expressed in E. coli as GST fusion, purified, and tested in dual-luciferase AP-1 reporter assay","journal":"Frontiers in bioscience (Elite edition)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — recombinant protein functional validation in reporter assay, localization confirmed, single lab","pmids":["20515784"],"is_preprint":false},{"year":2008,"finding":"AC3-33 (C3orf33/MISO1) encodes a 251 amino acid protein with no homology to other known proteins, localizes to the cytoplasm, and suppresses PMA/ionomycin-induced AP-1 activation when overexpressed.","method":"High-throughput cell-based screening of 650 function-known genes, subcellular localization studies, molecular cloning","journal":"Yi chuan = Hereditas","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (reporter screen), no mechanistic dissection beyond AP-1 suppression","pmids":["18487146"],"is_preprint":false},{"year":2019,"finding":"A splice variant of AC3-33 (svAC3-33, lacking exon 2, encoding 294 amino acids) localizes to the cytoplasm, inhibits MCF-7 breast cancer cell proliferation, upregulates p21 expression, and suppresses AP-1 activity by downregulating c-Jun but not c-Fos.","method":"RT-PCR cloning from MCF-7 cells, fluorescence localization, CCK-8 and EdU proliferation assays, RNAi knockdown, luciferase reporter assay, Western blotting","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple orthogonal assays (proliferation, knockdown, reporter, Western), describes a splice variant of the canonical gene","pmids":["31853289"],"is_preprint":false},{"year":2025,"finding":"MISO (C3orf33/MISO1) is an integral inner mitochondrial membrane (IMM) protein that (1) inhibits mitochondrial fusion by recruiting MTFP1 and excluding OPA1, (2) promotes fission through the FIS1-DRP1 pathway, (3) drives biogenesis of small MTFP1-enriched mitochondria (SMEM), and (4) facilitates peripheral fission of SMEM leading to lysosomal degradation of damaged mtDNA. Under basal conditions MISO is rapidly turned over; IMM stresses (mtDNA damage, OXPHOS dysfunction, cristae disruption) stabilize MISO, triggering SMEM assembly via its C-terminal domain, likely through oligomerization. Genetic ablation of MISO abolishes SMEM generation.","method":"Drosophila genetics (miso mutants), mammalian cell CRISPR/KO, live-cell fluorescence imaging, co-immunoprecipitation (MTFP1, FIS1, DRP1, OPA1 interactions), mitochondrial fractionation, mtDNA damage assays, OXPHOS dysfunction assays, domain mutagenesis (C-terminal deletion)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction studies, genetic ablation in two model systems (Drosophila and mammalian cells), multiple orthogonal functional readouts, domain mutagenesis, single rigorous study with comprehensive mechanistic dissection","pmids":["41398051"],"is_preprint":false},{"year":2026,"finding":"C3orf33/MISO is an integral IMM protein that assembles into SMEM subdomains under IMM stress, promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway, suppresses fusion via OPA1 exclusion, and directs damaged mtDNA to lysosomes via mitophagy. Under basal conditions MISO is rapidly turned over; specific IMM stresses stabilize it to initiate SMEM assembly.","method":"Genetic studies in Drosophila and mammalian cells, co-immunoprecipitation, mitochondrial subfractionation, live imaging, mtDNA damage and mitophagy assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent corroboration of findings from PMID 41398051 by the same group with additional mechanistic detail on OPA1 exclusion and mitophagy, multiple orthogonal methods across two model systems","pmids":["41568773"],"is_preprint":false}],"current_model":"MISO1 (C3orf33/AC3-33) encodes a conserved integral inner mitochondrial membrane protein that, under basal conditions is rapidly turned over, but upon inner membrane stress (mtDNA damage, OXPHOS dysfunction, or cristae disruption) is stabilized and oligomerizes via its C-terminal domain to nucleate small MTFP1-enriched mitochondria (SMEM) subdomains; mechanistically, MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1–DRP1 axis while suppressing fusion through OPA1 exclusion, and the resulting peripheral SMEM facilitate lysosomal clearance of damaged mtDNA via mitophagy; additionally, overexpression studies in human cells showed that MISO/AC3-33 is a cytoplasmic secretory protein that suppresses AP-1 transcriptional activity by reducing ERK1/2 phosphorylation, thereby inhibiting Elk1 and c-Jun but not c-Fos."},"narrative":{"mechanistic_narrative":"MISO1 (C3orf33/AC3-33) encodes a conserved integral inner mitochondrial membrane protein that governs stress-induced mitochondrial fission and quality control [PMID:41398051]. Under basal conditions MISO is rapidly turned over, but inner-membrane stresses—mtDNA damage, OXPHOS dysfunction, or cristae disruption—stabilize the protein and trigger assembly of small MTFP1-enriched mitochondria (SMEM) subdomains through its C-terminal domain [PMID:41398051]. Mechanistically, MISO recruits MTFP1 to activate the FIS1–DRP1(DNM1L) fission pathway while excluding OPA1 to suppress fusion, and the resulting peripheral SMEM undergo fission and are routed to lysosomes for mitophagic clearance of damaged mtDNA; genetic ablation in Drosophila and mammalian cells abolishes SMEM formation [PMID:41398051, PMID:41568773]. An earlier line of overexpression work characterized AC3-33 as a cytoplasmic, secretory protein that suppresses AP-1 transcriptional activity by reducing ERK1/2 phosphorylation, thereby inhibiting Elk1 and c-Jun but not c-Fos [PMID:20680465, PMID:20515784], with a splice variant additionally restraining MCF-7 proliferation and upregulating p21 [PMID:31853289]. The relationship between this reported cytoplasmic/secretory AP-1 activity and the mitochondrial fission role has not been reconciled in the available corpus.","teleology":[{"year":2008,"claim":"Initial functional screening assigned a phenotype to an otherwise uncharacterized ORF, establishing AC3-33 as a suppressor of AP-1 transcriptional activation.","evidence":"High-throughput cell-based reporter screen of function-known genes plus molecular cloning and subcellular localization in cells","pmids":["18487146"],"confidence":"Low","gaps":["No mechanistic dissection beyond AP-1 suppression","Overexpression only; no loss-of-function validation","Localization not linked to a defined activity"]},{"year":2010,"claim":"The AP-1 suppression was traced to a specific signaling node, showing AC3-33 acts upstream by reducing ERK1/2 phosphorylation rather than affecting JNK or p38.","evidence":"Overexpression with dual-luciferase AP-1 reporter, phospho-ERK1/2 Western blots, AP-1 DNA-binding assay, and recombinant GST-fusion protein functional testing","pmids":["20680465","20515784"],"confidence":"Medium","gaps":["Relies on overexpression without rescue or mutagenesis","Mechanism by which the protein modulates ERK1/2 unresolved","Secretory/signal-sequence role not mechanistically linked to intracellular ERK suppression"]},{"year":2019,"claim":"A splice variant extended the AP-1 axis to a growth-control output, linking AC3-33 to suppression of breast cancer cell proliferation via c-Jun downregulation and p21 induction.","evidence":"RT-PCR cloning from MCF-7 cells, proliferation assays (CCK-8, EdU), RNAi knockdown, luciferase reporter, and Western blotting","pmids":["31853289"],"confidence":"Medium","gaps":["Single cell line and single lab","Variant-specific versus canonical-isoform contributions not separated","No in vivo validation"]},{"year":2025,"claim":"A comprehensive mitochondrial study redefined the protein as an integral inner-membrane factor that nucleates stress-induced fission, establishing the MTFP1/FIS1-DRP1 recruitment and OPA1-exclusion mechanism and its role in clearing damaged mtDNA.","evidence":"Drosophila miso mutants, mammalian CRISPR knockout, live-cell imaging, reciprocal co-immunoprecipitation of MTFP1/FIS1/DRP1/OPA1, mitochondrial fractionation, mtDNA damage and OXPHOS assays, and C-terminal domain mutagenesis","pmids":["41398051"],"confidence":"High","gaps":["Molecular basis of stress-triggered stabilization not defined","Direct evidence for C-terminal oligomerization incomplete","Relationship to the earlier cytoplasmic/secretory AP-1 role unaddressed"]},{"year":2026,"claim":"Independent corroboration reinforced the fission and mitophagy model, adding detail on OPA1 exclusion and lysosomal routing of damaged mtDNA via mitophagy.","evidence":"Genetic studies in Drosophila and mammalian cells, co-immunoprecipitation, mitochondrial subfractionation, live imaging, and mtDNA damage/mitophagy assays","pmids":["41568773"],"confidence":"High","gaps":["Mitophagy receptor and machinery engaged downstream of SMEM not identified","Sensor distinguishing the different IMM stresses unknown"]},{"year":null,"claim":"Whether the cytoplasmic/secretory AP-1-suppressing activity and the inner-membrane fission role represent two functions of one protein, isoform-specific behaviors, or an unresolved discrepancy remains open.","evidence":"","pmids":[],"confidence":"High","gaps":["No study reconciles cytoplasmic secretory localization with integral IMM localization","ERK/AP-1 modulation has not been re-examined in the mitochondrial framework"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,2,3]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":[],"partners":["MTFP1","FIS1","DNM1L","OPA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"C3ORF33","url":"https://depmap.org/portal/gene/C3ORF33"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MISO1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"C3ORF33","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C3ORF33"},"hgnc":{"alias_symbol":["MISO","FLJ31139","AC3-33"],"prev_symbol":["C3orf33"]},"alphafold":{},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MISO1","jax_strain_url":"https://www.jax.org/strain/search?query=MISO1"},"sequence":{}},"corpus_meta":[{"pmid":"17119644","id":"PMC_17119644","title":"From miso, saké and shoyu to cosmetics: a century of science for kojic acid.","date":"2006","source":"Natural product reports","url":"https://pubmed.ncbi.nlm.nih.gov/17119644","citation_count":122,"is_preprint":false},{"pmid":"21056487","id":"PMC_21056487","title":"Simultaneous positron emission tomography (PET) assessment of metabolism with ¹⁸F-fluoro-2-deoxy-d-glucose (FDG), proliferation with ¹⁸F-fluoro-thymidine (FLT), and hypoxia with ¹⁸fluoro-misonidazole (F-miso) before and during radiotherapy in patients with non-small-cell lung cancer (NSCLC): a pilot study.","date":"2010","source":"Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21056487","citation_count":101,"is_preprint":false},{"pmid":"10879475","id":"PMC_10879475","title":"1,1-Diphenyl-2-picrylhydrazyl radical-scavenging compounds from soybean miso and antiproliferative activity of isoflavones from soybean miso toward the cancer cell lines.","date":"2000","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10879475","citation_count":66,"is_preprint":false},{"pmid":"39815104","id":"PMC_39815104","title":"Resolving tissue complexity by multimodal spatial omics modeling with MISO.","date":"2025","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/39815104","citation_count":40,"is_preprint":false},{"pmid":"11513643","id":"PMC_11513643","title":"Isoflavone transformation during soybean koji preparation and subsequent miso fermentation supplemented with ethanol and NaCl.","date":"2001","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11513643","citation_count":40,"is_preprint":false},{"pmid":"17284850","id":"PMC_17284850","title":"The formation mechanism by yeast of 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone in Miso.","date":"2007","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17284850","citation_count":31,"is_preprint":false},{"pmid":"22261579","id":"PMC_22261579","title":"Japanese traditional miso soup attenuates salt-induced hypertension and its organ damage in Dahl salt-sensitive rats.","date":"2012","source":"Nutrition (Burbank, Los Angeles County, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/22261579","citation_count":31,"is_preprint":false},{"pmid":"19619856","id":"PMC_19619856","title":"Release of antihypertensive peptides in miso paste during its fermentation, by the addition of casein.","date":"2009","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/19619856","citation_count":29,"is_preprint":false},{"pmid":"3759565","id":"PMC_3759565","title":"Phase II trial of misonidazole (MISO) and cyclophosphamide (CYC) in metastatic renal cell carcinoma.","date":"1986","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/3759565","citation_count":24,"is_preprint":false},{"pmid":"9543712","id":"PMC_9543712","title":"Binding of heterocyclic amines by lactic acid bacteria from miso, a fermented Japanese food.","date":"1998","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9543712","citation_count":24,"is_preprint":false},{"pmid":"30586377","id":"PMC_30586377","title":"Isolation of immune-regulatory Tetragenococcus halophilus from miso.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30586377","citation_count":20,"is_preprint":false},{"pmid":"16495649","id":"PMC_16495649","title":"Identification and typing of miso and soy sauce fermentation yeasts, Candida etchellsii and C. versatilis, based on sequence analyses of the D1D2 domain of the 26S ribosomal RNA gene, and the region of internal transcribed spacer 1, 5.8S ribosomal RNA gene and internal transcribed spacer 2.","date":"2006","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16495649","citation_count":19,"is_preprint":false},{"pmid":"20680465","id":"PMC_20680465","title":"AC3-33, a novel secretory protein, inhibits Elk1 transcriptional activity via ERK pathway.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20680465","citation_count":18,"is_preprint":false},{"pmid":"30845686","id":"PMC_30845686","title":"Miso (Fermented Soybean Paste) Suppresses Visceral Fat Accumulation in Mice, Especially in Combination with Exercise.","date":"2019","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/30845686","citation_count":18,"is_preprint":false},{"pmid":"10375131","id":"PMC_10375131","title":"Fermentation of low-salt miso as affected by supplementation with ethanol.","date":"1999","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10375131","citation_count":18,"is_preprint":false},{"pmid":"30123052","id":"PMC_30123052","title":"Inhibitory effect of Japanese rice-koji miso extracts on hepatitis A virus replication in association with the elevation of glucose-regulated protein 78 expression.","date":"2018","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30123052","citation_count":17,"is_preprint":false},{"pmid":"19615046","id":"PMC_19615046","title":"PCI-SS: MISO dynamic nonlinear protein secondary structure prediction.","date":"2009","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/19615046","citation_count":16,"is_preprint":false},{"pmid":"16273256","id":"PMC_16273256","title":"Decrease in size of azoxymethane induced colon carcinoma in F344 rats by 180-day fermented miso.","date":"2005","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16273256","citation_count":14,"is_preprint":false},{"pmid":"7107390","id":"PMC_7107390","title":"Enhancement of cytotoxic drugs by misonidazole (MISO) in Lewis lung tumors of different sizes, and mouse bone marrow.","date":"1982","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/7107390","citation_count":14,"is_preprint":false},{"pmid":"18776675","id":"PMC_18776675","title":"Genotyping of a miso and soy sauce fermentation yeast, Zygosaccharomyces rouxii, based on sequence analysis of the partial 26S ribosomal RNA gene and two internal transcribed spacers.","date":"2008","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18776675","citation_count":13,"is_preprint":false},{"pmid":"15973045","id":"PMC_15973045","title":"Rice allergenic proteins, 14-16 kDa albumin and alpha-globulin, remain insoluble in rice grains recovered from rice miso (rice-containing fermented soybean paste).","date":"2005","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15973045","citation_count":13,"is_preprint":false},{"pmid":"29678527","id":"PMC_29678527","title":"The Effect of Neoadjuvant Androgen Deprivation Therapy on Tumor Hypoxia in High-Grade Prostate Cancer: An 18F-MISO PET-MRI Study.","date":"2018","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/29678527","citation_count":12,"is_preprint":false},{"pmid":"31371810","id":"PMC_31371810","title":"Long-term intake of miso soup decreases nighttime blood pressure in subjects with high-normal blood pressure or stage I hypertension.","date":"2019","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/31371810","citation_count":12,"is_preprint":false},{"pmid":"3759561","id":"PMC_3759561","title":"Cross-link formation and chemopotentiation of EMT-6/Ro cells exposed to MISO after CCNU treatment in vitro.","date":"1986","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/3759561","citation_count":12,"is_preprint":false},{"pmid":"34213612","id":"PMC_34213612","title":"Novel probiotic yeast from Miso promotes regulatory dendritic cell IL-10 production and attenuates DSS-induced colitis in mice.","date":"2021","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/34213612","citation_count":12,"is_preprint":false},{"pmid":"10851494","id":"PMC_10851494","title":"Tumor cell growth-inhibiting effect of melanoidins extracted from miso 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= Hukuoka acta medica","url":"https://pubmed.ncbi.nlm.nih.gov/24908908","citation_count":6,"is_preprint":false},{"pmid":"23973834","id":"PMC_23973834","title":"Reduction of the degradation activity of umami-enhancing purinic ribonucleotide supplement in miso by the targeted suppression of acid phosphatases in the Aspergillus oryzae starter culture.","date":"2013","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23973834","citation_count":6,"is_preprint":false},{"pmid":"6480449","id":"PMC_6480449","title":"Survival in subpopulations of cells derived from solid KHT sarcomas by centrifugal elutriation following treatment with CCNU and MISO.","date":"1984","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/6480449","citation_count":6,"is_preprint":false},{"pmid":"41398051","id":"PMC_41398051","title":"MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane 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Japanese miso-treated human RSa cells, possibly via GRP78 expression.","date":"2011","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21897041","citation_count":4,"is_preprint":false},{"pmid":"6480450","id":"PMC_6480450","title":"The effect in the KHT sarcoma of CCNU and MISO on cell cycle progression evaluated by flow-cytometry.","date":"1984","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/6480450","citation_count":4,"is_preprint":false},{"pmid":"24317058","id":"PMC_24317058","title":"Improved palatability and bio-functionality of super-hard rice by soaking in a barley-koji miso suspension.","date":"2013","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24317058","citation_count":4,"is_preprint":false},{"pmid":"29994259","id":"PMC_29994259","title":"Sum Rate of MISO Neuro-Spike Communication Channel With Constant Spiking 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recombinant protein expressed in E. coli as GST fusion, purified, and tested in dual-luciferase AP-1 reporter assay\",\n      \"journal\": \"Frontiers in bioscience (Elite edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — recombinant protein functional validation in reporter assay, localization confirmed, single lab\",\n      \"pmids\": [\"20515784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AC3-33 (C3orf33/MISO1) encodes a 251 amino acid protein with no homology to other known proteins, localizes to the cytoplasm, and suppresses PMA/ionomycin-induced AP-1 activation when overexpressed.\",\n      \"method\": \"High-throughput cell-based screening of 650 function-known genes, subcellular localization studies, molecular cloning\",\n      \"journal\": \"Yi chuan = Hereditas\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (reporter screen), no mechanistic dissection beyond AP-1 suppression\",\n      \"pmids\": [\"18487146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A splice variant of AC3-33 (svAC3-33, lacking exon 2, encoding 294 amino acids) localizes to the cytoplasm, inhibits MCF-7 breast cancer cell proliferation, upregulates p21 expression, and suppresses AP-1 activity by downregulating c-Jun but not c-Fos.\",\n      \"method\": \"RT-PCR cloning from MCF-7 cells, fluorescence localization, CCK-8 and EdU proliferation assays, RNAi knockdown, luciferase reporter assay, Western blotting\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple orthogonal assays (proliferation, knockdown, reporter, Western), describes a splice variant of the canonical gene\",\n      \"pmids\": [\"31853289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MISO (C3orf33/MISO1) is an integral inner mitochondrial membrane (IMM) protein that (1) inhibits mitochondrial fusion by recruiting MTFP1 and excluding OPA1, (2) promotes fission through the FIS1-DRP1 pathway, (3) drives biogenesis of small MTFP1-enriched mitochondria (SMEM), and (4) facilitates peripheral fission of SMEM leading to lysosomal degradation of damaged mtDNA. Under basal conditions MISO is rapidly turned over; IMM stresses (mtDNA damage, OXPHOS dysfunction, cristae disruption) stabilize MISO, triggering SMEM assembly via its C-terminal domain, likely through oligomerization. Genetic ablation of MISO abolishes SMEM generation.\",\n      \"method\": \"Drosophila genetics (miso mutants), mammalian cell CRISPR/KO, live-cell fluorescence imaging, co-immunoprecipitation (MTFP1, FIS1, DRP1, OPA1 interactions), mitochondrial fractionation, mtDNA damage assays, OXPHOS dysfunction assays, domain mutagenesis (C-terminal deletion)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction studies, genetic ablation in two model systems (Drosophila and mammalian cells), multiple orthogonal functional readouts, domain mutagenesis, single rigorous study with comprehensive mechanistic dissection\",\n      \"pmids\": [\"41398051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"C3orf33/MISO is an integral IMM protein that assembles into SMEM subdomains under IMM stress, promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway, suppresses fusion via OPA1 exclusion, and directs damaged mtDNA to lysosomes via mitophagy. Under basal conditions MISO is rapidly turned over; specific IMM stresses stabilize it to initiate SMEM assembly.\",\n      \"method\": \"Genetic studies in Drosophila and mammalian cells, co-immunoprecipitation, mitochondrial subfractionation, live imaging, mtDNA damage and mitophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent corroboration of findings from PMID 41398051 by the same group with additional mechanistic detail on OPA1 exclusion and mitophagy, multiple orthogonal methods across two model systems\",\n      \"pmids\": [\"41568773\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MISO1 (C3orf33/AC3-33) encodes a conserved integral inner mitochondrial membrane protein that, under basal conditions is rapidly turned over, but upon inner membrane stress (mtDNA damage, OXPHOS dysfunction, or cristae disruption) is stabilized and oligomerizes via its C-terminal domain to nucleate small MTFP1-enriched mitochondria (SMEM) subdomains; mechanistically, MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1–DRP1 axis while suppressing fusion through OPA1 exclusion, and the resulting peripheral SMEM facilitate lysosomal clearance of damaged mtDNA via mitophagy; additionally, overexpression studies in human cells showed that MISO/AC3-33 is a cytoplasmic secretory protein that suppresses AP-1 transcriptional activity by reducing ERK1/2 phosphorylation, thereby inhibiting Elk1 and c-Jun but not c-Fos.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MISO1 (C3orf33/AC3-33) encodes a conserved integral inner mitochondrial membrane protein that governs stress-induced mitochondrial fission and quality control [#4]. Under basal conditions MISO is rapidly turned over, but inner-membrane stresses—mtDNA damage, OXPHOS dysfunction, or cristae disruption—stabilize the protein and trigger assembly of small MTFP1-enriched mitochondria (SMEM) subdomains through its C-terminal domain [#4]. Mechanistically, MISO recruits MTFP1 to activate the FIS1–DRP1(DNM1L) fission pathway while excluding OPA1 to suppress fusion, and the resulting peripheral SMEM undergo fission and are routed to lysosomes for mitophagic clearance of damaged mtDNA; genetic ablation in Drosophila and mammalian cells abolishes SMEM formation [#4, #5]. An earlier line of overexpression work characterized AC3-33 as a cytoplasmic, secretory protein that suppresses AP-1 transcriptional activity by reducing ERK1/2 phosphorylation, thereby inhibiting Elk1 and c-Jun but not c-Fos [#0, #1], with a splice variant additionally restraining MCF-7 proliferation and upregulating p21 [#3]. The relationship between this reported cytoplasmic/secretory AP-1 activity and the mitochondrial fission role has not been reconciled in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Initial functional screening assigned a phenotype to an otherwise uncharacterized ORF, establishing AC3-33 as a suppressor of AP-1 transcriptional activation.\",\n      \"evidence\": \"High-throughput cell-based reporter screen of function-known genes plus molecular cloning and subcellular localization in cells\",\n      \"pmids\": [\"18487146\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic dissection beyond AP-1 suppression\", \"Overexpression only; no loss-of-function validation\", \"Localization not linked to a defined activity\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The AP-1 suppression was traced to a specific signaling node, showing AC3-33 acts upstream by reducing ERK1/2 phosphorylation rather than affecting JNK or p38.\",\n      \"evidence\": \"Overexpression with dual-luciferase AP-1 reporter, phospho-ERK1/2 Western blots, AP-1 DNA-binding assay, and recombinant GST-fusion protein functional testing\",\n      \"pmids\": [\"20680465\", \"20515784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relies on overexpression without rescue or mutagenesis\", \"Mechanism by which the protein modulates ERK1/2 unresolved\", \"Secretory/signal-sequence role not mechanistically linked to intracellular ERK suppression\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A splice variant extended the AP-1 axis to a growth-control output, linking AC3-33 to suppression of breast cancer cell proliferation via c-Jun downregulation and p21 induction.\",\n      \"evidence\": \"RT-PCR cloning from MCF-7 cells, proliferation assays (CCK-8, EdU), RNAi knockdown, luciferase reporter, and Western blotting\",\n      \"pmids\": [\"31853289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line and single lab\", \"Variant-specific versus canonical-isoform contributions not separated\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A comprehensive mitochondrial study redefined the protein as an integral inner-membrane factor that nucleates stress-induced fission, establishing the MTFP1/FIS1-DRP1 recruitment and OPA1-exclusion mechanism and its role in clearing damaged mtDNA.\",\n      \"evidence\": \"Drosophila miso mutants, mammalian CRISPR knockout, live-cell imaging, reciprocal co-immunoprecipitation of MTFP1/FIS1/DRP1/OPA1, mitochondrial fractionation, mtDNA damage and OXPHOS assays, and C-terminal domain mutagenesis\",\n      \"pmids\": [\"41398051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of stress-triggered stabilization not defined\", \"Direct evidence for C-terminal oligomerization incomplete\", \"Relationship to the earlier cytoplasmic/secretory AP-1 role unaddressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Independent corroboration reinforced the fission and mitophagy model, adding detail on OPA1 exclusion and lysosomal routing of damaged mtDNA via mitophagy.\",\n      \"evidence\": \"Genetic studies in Drosophila and mammalian cells, co-immunoprecipitation, mitochondrial subfractionation, live imaging, and mtDNA damage/mitophagy assays\",\n      \"pmids\": [\"41568773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mitophagy receptor and machinery engaged downstream of SMEM not identified\", \"Sensor distinguishing the different IMM stresses unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the cytoplasmic/secretory AP-1-suppressing activity and the inner-membrane fission role represent two functions of one protein, isoform-specific behaviors, or an unresolved discrepancy remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No study reconciles cytoplasmic secretory localization with integral IMM localization\", \"ERK/AP-1 modulation has not been re-examined in the mitochondrial framework\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTFP1\", \"FIS1\", \"DNM1L\", \"OPA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":4,"faith_pct":75.0}}