{"gene":"CHCHD6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2007,"finding":"CHCHD6 was identified as a component of a mitochondrial inner membrane complex containing mitofilin, SAM50, metaxins 1 and 2, CHCHD3, and DnaJC11, immunocaptured via anti-mitofilin monoclonal antibody.","method":"Immunoprecipitation with anti-mitofilin monoclonal antibody followed by protein identification","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP establishing complex membership, single lab, single method","pmids":["17624330"],"is_preprint":false},{"year":2012,"finding":"CHCHD6 (CHCM1) localizes predominantly to the mitochondrial inner membrane; its knockdown causes severe defects in mitochondrial cristae morphology (hollow cristae with loss of structural definition and reduction in electron-dense matrix), reduces cell growth, ATP production, and oxygen consumption.","method":"Knockdown by siRNA, transmission electron microscopy, ATP assay, oxygen consumption measurement, immunofluorescence/fractionation for localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal functional readouts (TEM, ATP, O2 consumption, localization), single lab","pmids":["22228767"],"is_preprint":false},{"year":2012,"finding":"CHCHD6 directly interacts with mitofilin through its C-terminal coiled-coil-helix-coiled-coil-helix domain, and also interacts with CHCHD3 and DISC1; knockdown of CHCHD6 reduces mitofilin protein levels, and mitofilin knockdown reciprocally reduces CHCHD6 levels, indicating coordinate regulation.","method":"Co-immunoprecipitation, domain-mapping experiments, reciprocal knockdown/immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and reciprocal knockdown epistasis, single lab, multiple orthogonal methods","pmids":["22228767"],"is_preprint":false},{"year":2012,"finding":"CHCHD6 knockdown in human cancer cells enhances chemosensitivity to genotoxic anticancer drugs, while its overexpression increases resistance, linking CHCHD6 to drug response via mitochondrial integrity.","method":"siRNA knockdown and overexpression in cancer cell lines, drug sensitivity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD/OE with phenotypic readout but limited pathway mechanistic detail, single lab","pmids":["22228767"],"is_preprint":false},{"year":2015,"finding":"CHCHD6 (Mic25) is a peripheral subunit of the human MICOS complex; its depletion does not affect cristae morphology or stability of other MICOS components, in contrast to core subunits Mic60, Mic19, and Sam50.","method":"siRNA knockdown cell lines, transmission electron microscopy, immunoblotting of MICOS components","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with TEM and biochemical readouts, single lab, contradicts some other findings on cristae defects","pmids":["25781180"],"is_preprint":false},{"year":2015,"finding":"CHCHD6 physically interacts directly with Sam50 (outer membrane) and mitofilin (inner membrane); TALEN-generated CHCHD6 knockout cells show lower cristae density but maintained mitochondrial membrane potential and ATP content (in contrast to mitofilin knockdown), and knockout of CHCHD6 does not destabilize other MICOS binding partners.","method":"Co-immunoprecipitation, TALEN-based knockout, transmission electron microscopy, mitochondrial membrane potential assay, ATP measurement, immunoblotting","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction confirmed by Co-IP, TALEN KO with TEM and functional assays, multiple orthogonal methods, replicates interaction findings from prior labs","pmids":["26530328"],"is_preprint":false},{"year":2015,"finding":"Loss of QIL1/MIC13 results in accumulation of a MIC60-MIC19-MIC25 (CHCHD6) sub-complex with degradation of MIC10, MIC26, and MIC27, establishing that CHCHD6/MIC25 is part of a stable MIC60-MIC19-MIC25 sub-module within MICOS.","method":"Quantitative proteomics after QIL1 depletion, Co-immunoprecipitation","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics plus Co-IP, single lab, findings about CHCHD6 sub-complex membership are secondary to the paper's main focus","pmids":["25997101"],"is_preprint":false},{"year":2016,"finding":"CHCHD10 resides with mitofilin, CHCHD3, and CHCHD6 within the MICOS complex; CHCHD10 mutations lead to MICOS complex disassembly and loss of cristae, demonstrating CHCHD6 is part of the functional MICOS assembly.","method":"Co-immunoprecipitation, patient fibroblast analysis, electron microscopy","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex membership corroborated by disease model, single lab but independently replicates MICOS membership","pmids":["26666268"],"is_preprint":false},{"year":2016,"finding":"MIC13 knockout cells retain the MIC60/MIC19/MIC25 (CHCHD6) subcomplex, but this subcomplex alone is not sufficient for crista junction formation, establishing that CHCHD6-containing subcomplex is necessary but not sufficient for CJ integrity.","method":"CRISPR/Cas9 knockout, complexome profiling, transmission electron microscopy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with complexome profiling and TEM, single lab, secondary finding about CHCHD6 subcomplex","pmids":["27479602"],"is_preprint":false},{"year":2018,"finding":"CHCHD6 (MIC25) undergoes N-myristoylation in vitro and in vivo; however, unlike MIC19, non-myristoylated G2A mutant of MIC25 is not impaired in mitochondrial targeting or membrane binding, indicating N-myristoylation of MIC25 is not required for its mitochondrial localization.","method":"In vitro and in vivo metabolic labeling, immunofluorescence, subcellular fractionation, G2A mutagenesis, co-immunoprecipitation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro/in vivo labeling with mutagenesis, single lab, clear negative result for functional role of modification in targeting","pmids":["30427857"],"is_preprint":false},{"year":2022,"finding":"CARD19 interacts with MICOS components MIC19, MIC25 (CHCHD6), and MIC60 as identified by mass spectrometry of immunoprecipitates from macrophages, and this interaction is partly dependent on a properly folded CARD domain.","method":"Co-immunoprecipitation, mass spectrometry, domain deletion analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS-confirmed Co-IP with domain-mapping, single lab, CHCHD6 interaction is one of several interactors identified","pmids":["35406738"],"is_preprint":false},{"year":2022,"finding":"CHCHD6 and APP bind and stabilize one another; the APP intracellular domain (AICD) fragment inhibits CHCHD6 transcription by binding its promoter; reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing; compensation for CHCHD6 loss in an AD mouse model reduces neuropathology and cognitive impairment.","method":"Co-immunoprecipitation, promoter binding assay, cellular and animal AD models, mouse behavioral testing, immunofluorescence","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, promoter binding, animal rescue), single lab","pmids":["36104602"],"is_preprint":false},{"year":2023,"finding":"Cardiac-specific knockdown of the Drosophila ortholog of CHCHD3/CHCHD6 (dCHCHD3/6) results in drastically compromised heart contractility, diminished sarcomeric actin and myosin levels, reduced cardiac ATP, and mitochondrial fission-fusion defects, consistent with a role in maintaining cristae morphology and ETC assembly.","method":"Drosophila cardiac-specific RNAi knockdown, heart contractility imaging, immunofluorescence for sarcomeric proteins, ATP measurement, mitochondrial morphology analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD in in vivo model with multiple orthogonal functional readouts, but Drosophila ortholog may represent both CHCHD3 and CHCHD6","pmids":["37404133"],"is_preprint":false},{"year":2025,"finding":"MIC25 (CHCHD6) stability is regulated via ubiquitin-dependent degradation through interaction with ubiquitin-conjugating enzyme UBC; Epimedin C disrupts the MIC25-UBC interaction, preventing MIC25 degradation and maintaining MICOS integrity, ATP production, and mitochondrial cristae structure in skeletal muscle.","method":"Proteomic analysis, co-immunoprecipitation, MIC25 overexpression and knockdown, functional assays for mitochondrial function and exercise performance in mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional rescue experiments and KD/OE, single lab, novel PTM regulatory mechanism","pmids":["40435285"],"is_preprint":false},{"year":2024,"finding":"Knockdown of Chchd6 (along with Mic60) in HepG2 cells lowers mitochondrial Ca2+ uptake and retention and induces oxidative stress, demonstrating a role for CHCHD6 in mitochondrial calcium handling and redox homeostasis.","method":"siRNA knockdown in HepG2 cells, mitochondrial Ca2+ assays, oxidative stress measurements","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single method per endpoint, combined knockdown (Mic60 + Chchd6) limits attribution to CHCHD6 specifically","pmids":["bio_10.1101_2024.06.20.599846"],"is_preprint":true}],"current_model":"CHCHD6 (MIC25) is a coiled-coil-helix-coiled-coil-helix domain protein of the mitochondrial inner membrane that functions as a peripheral subunit of the MICOS complex, where it directly binds mitofilin/MIC60, CHCHD3/MIC19, and Sam50 to help maintain mitochondrial cristae morphology, support cristae junction integrity, and sustain ATP production and oxygen consumption; it is subject to ubiquitin-dependent degradation regulated by its interaction with UBC, undergoes N-myristoylation that is not required for its mitochondrial targeting, and participates in a feedback loop with APP in Alzheimer's disease pathology via mutual stabilization and AICD-mediated transcriptional repression."},"narrative":{"mechanistic_narrative":"CHCHD6 (MIC25) is a coiled-coil-helix-coiled-coil-helix domain protein of the mitochondrial inner membrane that functions as a peripheral subunit of the MICOS complex governing cristae architecture and mitochondrial bioenergetics [PMID:22228767, PMID:25781180]. It was first identified in an inner-membrane assembly captured through mitofilin, containing SAM50, metaxins 1/2, CHCHD3, and DnaJC11 [PMID:17624330], and it directly binds mitofilin/MIC60 via its C-terminal CHCH domain as well as CHCHD3/MIC19 and the outer-membrane component Sam50, bridging inner and outer membranes; CHCHD6 and mitofilin reciprocally stabilize one another at the protein level [PMID:22228767, PMID:26530328]. Within MICOS, CHCHD6 belongs to a stable MIC60–MIC19–MIC25 sub-module that persists when MIC13/QIL1 is lost but is not by itself sufficient to form crista junctions [PMID:25997101, PMID:27479602]. Loss-of-function studies link CHCHD6 to cristae morphology, ATP production, oxygen consumption, mitochondrial calcium handling and redox homeostasis, and to chemosensitivity in cancer cells [PMID:22228767, PMID:bio_10.1101_2024.06.20.599846]. CHCHD6 stability is set by ubiquitin-dependent degradation through its interaction with the ubiquitin-conjugating enzyme UBC, and disrupting this interaction preserves MICOS integrity and mitochondrial function [PMID:40435285]. In Alzheimer's disease models, CHCHD6 and APP mutually bind and stabilize each other while the APP intracellular domain (AICD) represses CHCHD6 transcription, and restoring CHCHD6 reduces neuropathology and cognitive impairment [PMID:36104602].","teleology":[{"year":2007,"claim":"Established that CHCHD6 is a physical constituent of a defined mitochondrial inner-membrane assembly, placing an uncharacterized protein into a specific molecular context.","evidence":"Anti-mitofilin immunocapture and protein identification of the inner-membrane complex","pmids":["17624330"],"confidence":"Medium","gaps":["Did not define which subunits CHCHD6 directly contacts","No functional consequence of complex membership tested"]},{"year":2012,"claim":"Defined CHCHD6 as functionally required for cristae integrity and bioenergetics and mapped its direct binding to mitofilin, answering whether the protein is a passive passenger or a structural/regulatory subunit.","evidence":"siRNA knockdown with TEM, ATP and oxygen-consumption assays, Co-IP with CHCH domain mapping and reciprocal knockdown in human cells","pmids":["22228767"],"confidence":"High","gaps":["Mechanism coupling cristae loss to ATP/O2 decline not resolved","Interaction with DISC1 not functionally characterized"]},{"year":2015,"claim":"Reclassified CHCHD6 as a peripheral rather than core MICOS subunit and showed it bridges the inner membrane (mitofilin) to the outer membrane (Sam50), clarifying its position in the complex architecture.","evidence":"Co-IP, TALEN knockout, TEM, membrane potential and ATP assays, and complexome/proteomics after QIL1 depletion","pmids":["25781180","26530328","25997101"],"confidence":"High","gaps":["Discrepancy between knockdown (severe cristae defects) and knockout (milder phenotype) unexplained","Stoichiometry and assembly order within MICOS not defined"]},{"year":2016,"claim":"Showed CHCHD6 resides in a stable MIC60–MIC19–MIC25 sub-module that is necessary but not sufficient for crista junction formation, refining the assembly hierarchy of MICOS.","evidence":"MIC13/QIL1 knockout, complexome profiling, TEM, and patient fibroblast analysis in CHCHD10-mutant disease","pmids":["27479602","26666268"],"confidence":"Medium","gaps":["What additional factors complete crista junction formation not identified","Direct contribution of CHCHD6 within the sub-module untested"]},{"year":2018,"claim":"Determined that CHCHD6 is N-myristoylated but, unlike MIC19, does not require this modification for mitochondrial targeting, distinguishing the regulatory logic of paralogous MICOS subunits.","evidence":"In vitro/in vivo metabolic labeling, G2A mutagenesis, fractionation and immunofluorescence","pmids":["30427857"],"confidence":"Medium","gaps":["Functional purpose of CHCHD6 myristoylation unknown","Whether modification affects interactions or stability untested"]},{"year":2022,"claim":"Linked CHCHD6 to APP biology in Alzheimer's disease via mutual protein stabilization and AICD-mediated transcriptional repression, connecting a mitochondrial structural protein to neurodegenerative pathology.","evidence":"Co-IP, promoter-binding assay, cellular and mouse AD models with behavioral rescue","pmids":["36104602"],"confidence":"Medium","gaps":["Molecular basis of CHCHD6-APP binding not mapped","Single lab; AICD-promoter mechanism not independently confirmed"]},{"year":2022,"claim":"Identified CHCHD6 as part of a CARD19 interactome in macrophages, hinting at MICOS connections to immune signaling proteins.","evidence":"Co-IP, mass spectrometry and CARD domain-deletion analysis","pmids":["35406738"],"confidence":"Medium","gaps":["Functional consequence of CARD19-CHCHD6 interaction unknown","Directness of CHCHD6 contact not established"]},{"year":2023,"claim":"Demonstrated an in vivo physiological requirement for the CHCHD3/CHCHD6 ortholog in cardiac contractility and mitochondrial integrity, extending the cristae-maintenance role to tissue function.","evidence":"Drosophila cardiac-specific RNAi with contractility imaging, sarcomeric protein staining, ATP and mitochondrial morphology analysis","pmids":["37404133"],"confidence":"Medium","gaps":["Drosophila ortholog represents both CHCHD3 and CHCHD6, limiting attribution to CHCHD6","Mechanism linking cristae defects to sarcomere loss not resolved"]},{"year":2025,"claim":"Uncovered ubiquitin-dependent control of CHCHD6 stability through UBC, defining a post-translational mechanism that sets MICOS integrity and mitochondrial function.","evidence":"Proteomics, Co-IP, KD/OE, and Epimedin C disruption with mitochondrial and exercise-performance assays in mice","pmids":["40435285"],"confidence":"Medium","gaps":["E3 ligase directing CHCHD6 ubiquitination not identified","Physiological signals triggering degradation unknown"]},{"year":null,"claim":"How CHCHD6 mechanistically couples cristae architecture to calcium handling, redox balance, and disease-relevant phenotypes, and what defines its specific non-redundant role versus other MICOS subunits, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CHCHD6 within MICOS","Calcium/redox role rests on combined Mic60+Chchd6 knockdown in a preprint","E3 ligase and physiological degradation triggers unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,4,5]}],"localization":[],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,4,5]}],"complexes":["MICOS","MIC60-MIC19-MIC25 sub-module"],"partners":["IMMT","CHCHD3","SAMM50","APP","UBC","CARD19","DISC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BRQ6","full_name":"MICOS complex subunit MIC25","aliases":["Coiled-coil-helix cristae morphology protein 1","Coiled-coil-helix-coiled-coil-helix domain-containing protein 6"],"length_aa":235,"mass_kda":26.5,"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","subcellular_location":"Mitochondrion inner membrane; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9BRQ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHCHD6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHCHD6","total_profiled":1310},"omim":[{"mim_id":"616658","title":"MITOCHONDRIAL CONTACT SITE AND CRISTAE ORGANIZING SYSTEM, 13-KD SUBUNIT; MICOS13","url":"https://www.omim.org/entry/616658"},{"mim_id":"615634","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 6; CHCHD6","url":"https://www.omim.org/entry/615634"},{"mim_id":"613748","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 3; CHCHD3","url":"https://www.omim.org/entry/613748"},{"mim_id":"612058","title":"SAMM50 SORTING AND ASSEMBLY MACHINERY COMPONENT; SAMM50","url":"https://www.omim.org/entry/612058"},{"mim_id":"608555","title":"METAXIN 2; MTX2","url":"https://www.omim.org/entry/608555"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":62.3}],"url":"https://www.proteinatlas.org/search/CHCHD6"},"hgnc":{"alias_symbol":["MGC13016","PPP1R23","CHCM1","Mic25","MICOS25"],"prev_symbol":[]},"alphafold":{"accession":"Q9BRQ6","domains":[{"cath_id":"1.20.5","chopping":"130-188","consensus_level":"medium","plddt":96.1132,"start":130,"end":188},{"cath_id":"1.10.287","chopping":"199-234","consensus_level":"high","plddt":95.0964,"start":199,"end":234}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRQ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRQ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRQ6-F1-predicted_aligned_error_v6.png","plddt_mean":78.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHCHD6","jax_strain_url":"https://www.jax.org/strain/search?query=CHCHD6"},"sequence":{"accession":"Q9BRQ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRQ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRQ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRQ6"}},"corpus_meta":[{"pmid":"17624330","id":"PMC_17624330","title":"The 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membrane complex containing mitofilin, SAM50, metaxins 1 and 2, CHCHD3, and DnaJC11, immunocaptured via anti-mitofilin monoclonal antibody.\",\n      \"method\": \"Immunoprecipitation with anti-mitofilin monoclonal antibody followed by protein identification\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP establishing complex membership, single lab, single method\",\n      \"pmids\": [\"17624330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CHCHD6 (CHCM1) localizes predominantly to the mitochondrial inner membrane; its knockdown causes severe defects in mitochondrial cristae morphology (hollow cristae with loss of structural definition and reduction in electron-dense matrix), reduces cell growth, ATP production, and oxygen consumption.\",\n      \"method\": \"Knockdown by siRNA, transmission electron microscopy, ATP assay, oxygen consumption measurement, immunofluorescence/fractionation for localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal functional readouts (TEM, ATP, O2 consumption, localization), single lab\",\n      \"pmids\": [\"22228767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CHCHD6 directly interacts with mitofilin through its C-terminal coiled-coil-helix-coiled-coil-helix domain, and also interacts with CHCHD3 and DISC1; knockdown of CHCHD6 reduces mitofilin protein levels, and mitofilin knockdown reciprocally reduces CHCHD6 levels, indicating coordinate regulation.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments, reciprocal knockdown/immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and reciprocal knockdown epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22228767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CHCHD6 knockdown in human cancer cells enhances chemosensitivity to genotoxic anticancer drugs, while its overexpression increases resistance, linking CHCHD6 to drug response via mitochondrial integrity.\",\n      \"method\": \"siRNA knockdown and overexpression in cancer cell lines, drug sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD/OE with phenotypic readout but limited pathway mechanistic detail, single lab\",\n      \"pmids\": [\"22228767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHCHD6 (Mic25) is a peripheral subunit of the human MICOS complex; its depletion does not affect cristae morphology or stability of other MICOS components, in contrast to core subunits Mic60, Mic19, and Sam50.\",\n      \"method\": \"siRNA knockdown cell lines, transmission electron microscopy, immunoblotting of MICOS components\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with TEM and biochemical readouts, single lab, contradicts some other findings on cristae defects\",\n      \"pmids\": [\"25781180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHCHD6 physically interacts directly with Sam50 (outer membrane) and mitofilin (inner membrane); TALEN-generated CHCHD6 knockout cells show lower cristae density but maintained mitochondrial membrane potential and ATP content (in contrast to mitofilin knockdown), and knockout of CHCHD6 does not destabilize other MICOS binding partners.\",\n      \"method\": \"Co-immunoprecipitation, TALEN-based knockout, transmission electron microscopy, mitochondrial membrane potential assay, ATP measurement, immunoblotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction confirmed by Co-IP, TALEN KO with TEM and functional assays, multiple orthogonal methods, replicates interaction findings from prior labs\",\n      \"pmids\": [\"26530328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of QIL1/MIC13 results in accumulation of a MIC60-MIC19-MIC25 (CHCHD6) sub-complex with degradation of MIC10, MIC26, and MIC27, establishing that CHCHD6/MIC25 is part of a stable MIC60-MIC19-MIC25 sub-module within MICOS.\",\n      \"method\": \"Quantitative proteomics after QIL1 depletion, Co-immunoprecipitation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics plus Co-IP, single lab, findings about CHCHD6 sub-complex membership are secondary to the paper's main focus\",\n      \"pmids\": [\"25997101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHCHD10 resides with mitofilin, CHCHD3, and CHCHD6 within the MICOS complex; CHCHD10 mutations lead to MICOS complex disassembly and loss of cristae, demonstrating CHCHD6 is part of the functional MICOS assembly.\",\n      \"method\": \"Co-immunoprecipitation, patient fibroblast analysis, electron microscopy\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex membership corroborated by disease model, single lab but independently replicates MICOS membership\",\n      \"pmids\": [\"26666268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIC13 knockout cells retain the MIC60/MIC19/MIC25 (CHCHD6) subcomplex, but this subcomplex alone is not sufficient for crista junction formation, establishing that CHCHD6-containing subcomplex is necessary but not sufficient for CJ integrity.\",\n      \"method\": \"CRISPR/Cas9 knockout, complexome profiling, transmission electron microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with complexome profiling and TEM, single lab, secondary finding about CHCHD6 subcomplex\",\n      \"pmids\": [\"27479602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHCHD6 (MIC25) undergoes N-myristoylation in vitro and in vivo; however, unlike MIC19, non-myristoylated G2A mutant of MIC25 is not impaired in mitochondrial targeting or membrane binding, indicating N-myristoylation of MIC25 is not required for its mitochondrial localization.\",\n      \"method\": \"In vitro and in vivo metabolic labeling, immunofluorescence, subcellular fractionation, G2A mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro/in vivo labeling with mutagenesis, single lab, clear negative result for functional role of modification in targeting\",\n      \"pmids\": [\"30427857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CARD19 interacts with MICOS components MIC19, MIC25 (CHCHD6), and MIC60 as identified by mass spectrometry of immunoprecipitates from macrophages, and this interaction is partly dependent on a properly folded CARD domain.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, domain deletion analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS-confirmed Co-IP with domain-mapping, single lab, CHCHD6 interaction is one of several interactors identified\",\n      \"pmids\": [\"35406738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHCHD6 and APP bind and stabilize one another; the APP intracellular domain (AICD) fragment inhibits CHCHD6 transcription by binding its promoter; reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing; compensation for CHCHD6 loss in an AD mouse model reduces neuropathology and cognitive impairment.\",\n      \"method\": \"Co-immunoprecipitation, promoter binding assay, cellular and animal AD models, mouse behavioral testing, immunofluorescence\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, promoter binding, animal rescue), single lab\",\n      \"pmids\": [\"36104602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cardiac-specific knockdown of the Drosophila ortholog of CHCHD3/CHCHD6 (dCHCHD3/6) results in drastically compromised heart contractility, diminished sarcomeric actin and myosin levels, reduced cardiac ATP, and mitochondrial fission-fusion defects, consistent with a role in maintaining cristae morphology and ETC assembly.\",\n      \"method\": \"Drosophila cardiac-specific RNAi knockdown, heart contractility imaging, immunofluorescence for sarcomeric proteins, ATP measurement, mitochondrial morphology analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD in in vivo model with multiple orthogonal functional readouts, but Drosophila ortholog may represent both CHCHD3 and CHCHD6\",\n      \"pmids\": [\"37404133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MIC25 (CHCHD6) stability is regulated via ubiquitin-dependent degradation through interaction with ubiquitin-conjugating enzyme UBC; Epimedin C disrupts the MIC25-UBC interaction, preventing MIC25 degradation and maintaining MICOS integrity, ATP production, and mitochondrial cristae structure in skeletal muscle.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, MIC25 overexpression and knockdown, functional assays for mitochondrial function and exercise performance in mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional rescue experiments and KD/OE, single lab, novel PTM regulatory mechanism\",\n      \"pmids\": [\"40435285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of Chchd6 (along with Mic60) in HepG2 cells lowers mitochondrial Ca2+ uptake and retention and induces oxidative stress, demonstrating a role for CHCHD6 in mitochondrial calcium handling and redox homeostasis.\",\n      \"method\": \"siRNA knockdown in HepG2 cells, mitochondrial Ca2+ assays, oxidative stress measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single method per endpoint, combined knockdown (Mic60 + Chchd6) limits attribution to CHCHD6 specifically\",\n      \"pmids\": [\"bio_10.1101_2024.06.20.599846\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CHCHD6 (MIC25) is a coiled-coil-helix-coiled-coil-helix domain protein of the mitochondrial inner membrane that functions as a peripheral subunit of the MICOS complex, where it directly binds mitofilin/MIC60, CHCHD3/MIC19, and Sam50 to help maintain mitochondrial cristae morphology, support cristae junction integrity, and sustain ATP production and oxygen consumption; it is subject to ubiquitin-dependent degradation regulated by its interaction with UBC, undergoes N-myristoylation that is not required for its mitochondrial targeting, and participates in a feedback loop with APP in Alzheimer's disease pathology via mutual stabilization and AICD-mediated transcriptional repression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHCHD6 (MIC25) is a coiled-coil-helix-coiled-coil-helix domain protein of the mitochondrial inner membrane that functions as a peripheral subunit of the MICOS complex governing cristae architecture and mitochondrial bioenergetics [#1, #4]. It was first identified in an inner-membrane assembly captured through mitofilin, containing SAM50, metaxins 1/2, CHCHD3, and DnaJC11 [#0], and it directly binds mitofilin/MIC60 via its C-terminal CHCH domain as well as CHCHD3/MIC19 and the outer-membrane component Sam50, bridging inner and outer membranes; CHCHD6 and mitofilin reciprocally stabilize one another at the protein level [#2, #5]. Within MICOS, CHCHD6 belongs to a stable MIC60–MIC19–MIC25 sub-module that persists when MIC13/QIL1 is lost but is not by itself sufficient to form crista junctions [#6, #8]. Loss-of-function studies link CHCHD6 to cristae morphology, ATP production, oxygen consumption, mitochondrial calcium handling and redox homeostasis, and to chemosensitivity in cancer cells [#1, #3, #14]. CHCHD6 stability is set by ubiquitin-dependent degradation through its interaction with the ubiquitin-conjugating enzyme UBC, and disrupting this interaction preserves MICOS integrity and mitochondrial function [#13]. In Alzheimer's disease models, CHCHD6 and APP mutually bind and stabilize each other while the APP intracellular domain (AICD) represses CHCHD6 transcription, and restoring CHCHD6 reduces neuropathology and cognitive impairment [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that CHCHD6 is a physical constituent of a defined mitochondrial inner-membrane assembly, placing an uncharacterized protein into a specific molecular context.\",\n      \"evidence\": \"Anti-mitofilin immunocapture and protein identification of the inner-membrane complex\",\n      \"pmids\": [\"17624330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which subunits CHCHD6 directly contacts\", \"No functional consequence of complex membership tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined CHCHD6 as functionally required for cristae integrity and bioenergetics and mapped its direct binding to mitofilin, answering whether the protein is a passive passenger or a structural/regulatory subunit.\",\n      \"evidence\": \"siRNA knockdown with TEM, ATP and oxygen-consumption assays, Co-IP with CHCH domain mapping and reciprocal knockdown in human cells\",\n      \"pmids\": [\"22228767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling cristae loss to ATP/O2 decline not resolved\", \"Interaction with DISC1 not functionally characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reclassified CHCHD6 as a peripheral rather than core MICOS subunit and showed it bridges the inner membrane (mitofilin) to the outer membrane (Sam50), clarifying its position in the complex architecture.\",\n      \"evidence\": \"Co-IP, TALEN knockout, TEM, membrane potential and ATP assays, and complexome/proteomics after QIL1 depletion\",\n      \"pmids\": [\"25781180\", \"26530328\", \"25997101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy between knockdown (severe cristae defects) and knockout (milder phenotype) unexplained\", \"Stoichiometry and assembly order within MICOS not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CHCHD6 resides in a stable MIC60–MIC19–MIC25 sub-module that is necessary but not sufficient for crista junction formation, refining the assembly hierarchy of MICOS.\",\n      \"evidence\": \"MIC13/QIL1 knockout, complexome profiling, TEM, and patient fibroblast analysis in CHCHD10-mutant disease\",\n      \"pmids\": [\"27479602\", \"26666268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What additional factors complete crista junction formation not identified\", \"Direct contribution of CHCHD6 within the sub-module untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Determined that CHCHD6 is N-myristoylated but, unlike MIC19, does not require this modification for mitochondrial targeting, distinguishing the regulatory logic of paralogous MICOS subunits.\",\n      \"evidence\": \"In vitro/in vivo metabolic labeling, G2A mutagenesis, fractionation and immunofluorescence\",\n      \"pmids\": [\"30427857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional purpose of CHCHD6 myristoylation unknown\", \"Whether modification affects interactions or stability untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CHCHD6 to APP biology in Alzheimer's disease via mutual protein stabilization and AICD-mediated transcriptional repression, connecting a mitochondrial structural protein to neurodegenerative pathology.\",\n      \"evidence\": \"Co-IP, promoter-binding assay, cellular and mouse AD models with behavioral rescue\",\n      \"pmids\": [\"36104602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of CHCHD6-APP binding not mapped\", \"Single lab; AICD-promoter mechanism not independently confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CHCHD6 as part of a CARD19 interactome in macrophages, hinting at MICOS connections to immune signaling proteins.\",\n      \"evidence\": \"Co-IP, mass spectrometry and CARD domain-deletion analysis\",\n      \"pmids\": [\"35406738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CARD19-CHCHD6 interaction unknown\", \"Directness of CHCHD6 contact not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated an in vivo physiological requirement for the CHCHD3/CHCHD6 ortholog in cardiac contractility and mitochondrial integrity, extending the cristae-maintenance role to tissue function.\",\n      \"evidence\": \"Drosophila cardiac-specific RNAi with contractility imaging, sarcomeric protein staining, ATP and mitochondrial morphology analysis\",\n      \"pmids\": [\"37404133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Drosophila ortholog represents both CHCHD3 and CHCHD6, limiting attribution to CHCHD6\", \"Mechanism linking cristae defects to sarcomere loss not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered ubiquitin-dependent control of CHCHD6 stability through UBC, defining a post-translational mechanism that sets MICOS integrity and mitochondrial function.\",\n      \"evidence\": \"Proteomics, Co-IP, KD/OE, and Epimedin C disruption with mitochondrial and exercise-performance assays in mice\",\n      \"pmids\": [\"40435285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase directing CHCHD6 ubiquitination not identified\", \"Physiological signals triggering degradation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHCHD6 mechanistically couples cristae architecture to calcium handling, redox balance, and disease-relevant phenotypes, and what defines its specific non-redundant role versus other MICOS subunits, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CHCHD6 within MICOS\", \"Calcium/redox role rests on combined Mic60+Chchd6 knockdown in a preprint\", \"E3 ligase and physiological degradation triggers unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 4, 5]}\n    ],\n    \"complexes\": [\"MICOS\", \"MIC60-MIC19-MIC25 sub-module\"],\n    \"partners\": [\"IMMT\", \"CHCHD3\", \"SAMM50\", \"APP\", \"UBC\", \"CARD19\", \"DISC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}