{"gene":"DNAJC11","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2007,"finding":"DNAJC11 exists as part of a mitochondrial complex with mitofilin (inner membrane protein), SAM50, metaxins 1 and 2, CHCHD3, and CHCHD6, immunocaptured by a mitofilin monoclonal antibody, suggesting a role in protein import or maintenance of mitochondrial structure.","method":"Immunoprecipitation (monoclonal antibody immunocapture) followed by protein identification","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP identifying complex members, single study","pmids":["17624330"],"is_preprint":false},{"year":2014,"finding":"DNAJC11 localizes to the periphery of the mitochondrial outer membrane (full-length 63 kDa isoform), with putative additional isoforms showing differential submitochondrial localization; it is assembled in a high molecular weight complex similarly to mitofilin; downregulation of mitofilin or SAM50 reduces DNAJC11 protein levels, indicating DNAJC11 stability depends on MICOS complex members.","method":"Subcellular fractionation, immunofluorescence, western blotting after siRNA knockdown of mitofilin and SAM50 in HeLa cells; rescue experiments with human DNAJC11 overexpression in mutant mice","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, protein-level dependency, genetic rescue), single lab but comprehensive","pmids":["25111180"],"is_preprint":false},{"year":2014,"finding":"Loss-of-function (splice-site hypomorphic mutation) of DNAJC11 in mice causes motor neuron vacuolation arising from mitochondria with disorganized inner membrane cristae, as well as lymphoid abnormalities, establishing DNAJC11 as required for mitochondrial inner membrane organization in neurons.","method":"ENU forward genetics screen, neuropathological analysis (electron microscopy of motor neurons), genetic rescue with human DNAJC11 overexpression","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined cellular phenotype confirmed by genetic rescue, EM-level resolution","pmids":["25111180"],"is_preprint":false},{"year":2019,"finding":"DNAJC11 interacts with MICOS complex members (confirming cristae organization role), VDACs at the outer mitochondrial membrane, ribosomal subunits and Hsp70 chaperones in metabolically active cells (HEK293FT), and synaptic proteins in mouse cerebrum; the DUF3395 domain mediates protein-protein interactions while the J-domain determines mitochondrial localization.","method":"Affinity purification–mass spectrometry (DNAJC11-FLAG immunoprecipitation) in HEK293FT cells and transgenic mice; domain deletion/mutation analysis","journal":"Journal of proteome research","confidence":"High","confidence_rationale":"Tier 2 — MS-based interactome in two biological systems with domain-level mechanistic dissection","pmids":["31550165"],"is_preprint":false},{"year":2025,"finding":"DNAJC11 facilitates ARMC1 release from mitochondria; disrupting the ARMC1–DNAJC11 interaction leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial distribution defects, placing DNAJC11 as a regulator of ARMC1 mito-cytoplasmic shuttling that tunes steady-state mitochondrial distribution.","method":"Co-immunoprecipitation, genetic perturbation (ARMC1 deletion, disruption of DNAJC11–ARMC1 interaction), live-cell imaging of mitochondrial distribution","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional epistasis with imaging readout, single study","pmids":["40203102"],"is_preprint":false},{"year":2025,"finding":"DNAJC11 interacts with SARS-CoV-2 NSP3, stabilizes NSP3 protein through endogenous apoptosis pathways, and facilitates NSP3–NSP4 interaction, thereby promoting double-membrane vesicle (DMV) formation required for viral replication; DNAJC11 knockdown reduces DMV number and size, while DNAJC11 supplementation restores them.","method":"Mass spectrometry identification of interaction, co-immunoprecipitation, siRNA knockdown, ectopic overexpression, electron microscopy of DMVs","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (MS, Co-IP, KD/OE, EM), single study","pmids":["40872740"],"is_preprint":false}],"current_model":"DNAJC11 is a mitochondrial outer membrane chaperone-like protein whose J-domain directs mitochondrial localization and whose DUF3395 domain mediates protein–protein interactions; it assembles into the MICOS/MIB supercomplex with mitofilin, SAM50, metaxins, and CHCHD proteins to maintain mitochondrial cristae structure, regulates ARMC1 mito-cytoplasmic shuttling to control mitochondrial distribution, and can stabilize viral NSP3 to promote double-membrane vesicle formation, with loss of function causing cristae disorganization and motor neuron pathology in mice."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of DNAJC11 as a component of a mitofilin-containing mitochondrial complex with SAM50, metaxins, and CHCHD proteins established that DNAJC11 participates in a multi-subunit assembly at the mitochondrial membranes, raising the question of its specific contribution.","evidence":"Immunocapture with mitofilin monoclonal antibody followed by protein identification from mitochondrial extracts","pmids":["17624330"],"confidence":"Medium","gaps":["Single immunocapture study without reciprocal pull-down from DNAJC11 side","No functional consequence of DNAJC11 loss was tested","Topology and submitochondrial localization of DNAJC11 were undefined"]},{"year":2014,"claim":"Determination that DNAJC11 localizes to the mitochondrial outer membrane periphery, depends on mitofilin/SAM50 for stability, and is essential for cristae organization in motor neurons resolved its functional role: DNAJC11 is required for inner membrane architecture, and its loss causes neuronal vacuolation from cristae disorganization.","evidence":"Subcellular fractionation, immunofluorescence, siRNA knockdown of mitofilin/SAM50 in HeLa cells; ENU mutagenesis in mice with EM neuropathology and genetic rescue by human DNAJC11 overexpression","pmids":["25111180"],"confidence":"High","gaps":["Molecular mechanism by which DNAJC11 maintains cristae structure was not defined","Whether the J-domain chaperone activity is enzymatically required was untested","The human disease relevance of DNAJC11 loss-of-function was not established"]},{"year":2019,"claim":"Systematic interactome mapping and domain dissection revealed that the DUF3395 domain mediates DNAJC11 protein–protein interactions (including MICOS, VDACs, ribosomes, Hsp70) while the J-domain determines mitochondrial targeting, defining the modular logic of DNAJC11 function.","evidence":"AP-MS of DNAJC11-FLAG in HEK293FT cells and transgenic mouse cerebrum; domain deletion and mutation analysis","pmids":["31550165"],"confidence":"High","gaps":["Whether Hsp70 binding reflects active chaperone cycling or passive scaffolding is unknown","Functional significance of ribosomal and synaptic protein interactions was not tested","No structural model of DNAJC11 within the MICOS/MIB supercomplex exists"]},{"year":2025,"claim":"Discovery that DNAJC11 facilitates ARMC1 release from mitochondria to control mitochondrial distribution expanded its role beyond cristae maintenance to a regulator of organelle positioning.","evidence":"Co-IP, genetic perturbation of ARMC1–DNAJC11 interaction, live-cell imaging of mitochondrial distribution","pmids":["40203102"],"confidence":"Medium","gaps":["Single study; independent replication is needed","Mechanism by which DNAJC11 releases ARMC1 (chaperone activity vs. competitive binding) is undefined","Relationship between ARMC1-dependent distribution and cristae organization is unexplored"]},{"year":2025,"claim":"DNAJC11 was shown to stabilize SARS-CoV-2 NSP3 and promote NSP3–NSP4 interaction for double-membrane vesicle biogenesis, revealing that its chaperone-like activity can be co-opted during viral infection.","evidence":"MS-based interaction identification, Co-IP, siRNA knockdown and overexpression of DNAJC11, EM quantification of DMVs","pmids":["40872740"],"confidence":"Medium","gaps":["Single study on one viral system; breadth of host–pathogen relevance is unknown","Whether J-domain-dependent Hsp70 cycling is required for NSP3 stabilization is untested","Impact on viral replication titers was not reported"]},{"year":null,"claim":"The catalytic contribution of DNAJC11's J-domain chaperone cycle (Hsp70 co-chaperone activity) versus its scaffolding function within the MICOS/MIB supercomplex remains mechanistically unresolved, and no human Mendelian disease has been linked to DNAJC11 mutations.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstitution of DNAJC11 J-domain stimulated ATPase activity with Hsp70 has been performed","No structural data for DNAJC11 or its complexes exist","Human genetic loss-of-function consequences are uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,3]}],"complexes":["MICOS/MIB supercomplex"],"partners":["IMMT","SAMM50","MTX1","MTX2","CHCHD3","CHCHD6","ARMC1"],"other_free_text":[]},"mechanistic_narrative":"DNAJC11 is a mitochondrial outer membrane J-domain protein that maintains mitochondrial cristae architecture and regulates mitochondrial distribution. It assembles into a high-molecular-weight supercomplex with MICOS components (mitofilin, CHCHD3, CHCHD6), SAM50, metaxins, and VDACs, where its DUF3395 domain mediates protein–protein interactions and its J-domain directs mitochondrial localization; its stability depends on mitofilin and SAM50 [PMID:17624330, PMID:25111180, PMID:31550165]. Loss of DNAJC11 in mice causes motor neuron vacuolation with disorganized inner membrane cristae and lymphoid abnormalities, a phenotype rescued by human DNAJC11 overexpression [PMID:25111180]. DNAJC11 also regulates ARMC1 release from mitochondria to tune mitochondrial distribution [PMID:40203102] and can stabilize SARS-CoV-2 NSP3 to promote double-membrane vesicle formation during viral replication [PMID:40872740]."},"prefetch_data":{"uniprot":{"accession":"Q9NVH1","full_name":"DnaJ homolog subfamily C member 11","aliases":[],"length_aa":559,"mass_kda":63.3,"function":"Required for mitochondrial inner membrane organization. Seems to function through its association with the MICOS complex and the mitochondrial outer membrane sorting assembly machinery (SAM) complex","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q9NVH1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJC11","classification":"Not Classified","n_dependent_lines":759,"n_total_lines":1208,"dependency_fraction":0.6283112582781457},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000007923","cell_line_id":"CID000022","localizations":[{"compartment":"mitochondria","grade":3}],"interactors":[{"gene":"MTX1","stoichiometry":10.0},{"gene":"IMMT","stoichiometry":4.0},{"gene":"ARMC1","stoichiometry":4.0},{"gene":"SAMM50","stoichiometry":4.0},{"gene":"APOO","stoichiometry":4.0},{"gene":"CHCHD3","stoichiometry":4.0},{"gene":"TOMM20","stoichiometry":0.2},{"gene":"MTCH2","stoichiometry":0.2},{"gene":"VDAC2","stoichiometry":0.2},{"gene":"VCP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000022","total_profiled":1310},"omim":[{"mim_id":"615634","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 6; CHCHD6","url":"https://www.omim.org/entry/615634"},{"mim_id":"614827","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 11; DNAJC11","url":"https://www.omim.org/entry/614827"},{"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"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNAJC11"},"hgnc":{"alias_symbol":["FLJ10737"],"prev_symbol":[]},"alphafold":{"accession":"Q9NVH1","domains":[{"cath_id":"1.10.287.110","chopping":"8-71","consensus_level":"high","plddt":84.0155,"start":8,"end":71},{"cath_id":"-","chopping":"428-554","consensus_level":"high","plddt":84.8142,"start":428,"end":554}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVH1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVH1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVH1-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAJC11","jax_strain_url":"https://www.jax.org/strain/search?query=DNAJC11"},"sequence":{"accession":"Q9NVH1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVH1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVH1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVH1"}},"corpus_meta":[{"pmid":"17624330","id":"PMC_17624330","title":"The mitochondrial inner membrane protein mitofilin exists as a complex with SAM50, metaxins 1 and 2, coiled-coil-helix coiled-coil-helix domain-containing protein 3 and 6 and DnaJC11.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17624330","citation_count":179,"is_preprint":false},{"pmid":"26477565","id":"PMC_26477565","title":"Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26477565","citation_count":159,"is_preprint":false},{"pmid":"28709640","id":"PMC_28709640","title":"Genome-wide identification of genes essential for podocyte cytoskeletons based on single-cell RNA sequencing.","date":"2017","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/28709640","citation_count":69,"is_preprint":false},{"pmid":"12964007","id":"PMC_12964007","title":"Identification and characterization of FLJ10737 and CAMTA1 genes on the commonly deleted region of neuroblastoma at human chromosome 1p36.31-p36.23.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12964007","citation_count":62,"is_preprint":false},{"pmid":"16397034","id":"PMC_16397034","title":"Reduced expression of CAMTA1 correlates with adverse outcome in neuroblastoma patients.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/16397034","citation_count":53,"is_preprint":false},{"pmid":"25111180","id":"PMC_25111180","title":"A splicing mutation in the novel mitochondrial protein DNAJC11 causes motor neuron pathology associated with cristae disorganization, and lymphoid abnormalities in mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25111180","citation_count":42,"is_preprint":false},{"pmid":"27065250","id":"PMC_27065250","title":"The evolution of MICOS: Ancestral and derived functions and interactions.","date":"2015","source":"Communicative & integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/27065250","citation_count":29,"is_preprint":false},{"pmid":"31550165","id":"PMC_31550165","title":"Mapping Interactome Networks of DNAJC11, a Novel Mitochondrial Protein Causing Neuromuscular Pathology in Mice.","date":"2019","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/31550165","citation_count":12,"is_preprint":false},{"pmid":"17222547","id":"PMC_17222547","title":"Allelic variants of CAMTA1 and FLJ10737 within a commonly deleted region at 1p36 in neuroblastoma.","date":"2007","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/17222547","citation_count":10,"is_preprint":false},{"pmid":"27081464","id":"PMC_27081464","title":"Down-regulation of HSP40 gene family following OCT4B1 suppression in human tumor cell lines.","date":"2016","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27081464","citation_count":8,"is_preprint":false},{"pmid":"40203102","id":"PMC_40203102","title":"ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/40203102","citation_count":4,"is_preprint":false},{"pmid":"41719330","id":"PMC_41719330","title":"Human lncRNA RMRP interacts with DEAD-box helicases and modulates mitochondrial function.","date":"2026","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41719330","citation_count":1,"is_preprint":false},{"pmid":"40872740","id":"PMC_40872740","title":"DNAJ Homolog Subfamily C Member 11 Stabilizes SARS-CoV-2 NSP3 to Promote Double-Membrane Vesicle Formation.","date":"2025","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/40872740","citation_count":0,"is_preprint":false},{"pmid":"41951985","id":"PMC_41951985","title":"The genetic associations of DNAJC family members with Parkinson's disease: comprehensive evidence from burden analysis and Mendelian randomization.","date":"2026","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41951985","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8365,"output_tokens":1566,"usd":0.024293},"stage2":{"model":"claude-opus-4-6","input_tokens":4817,"output_tokens":1883,"usd":0.10674},"total_usd":0.131033,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"DNAJC11 exists as part of a mitochondrial complex with mitofilin (inner membrane protein), SAM50, metaxins 1 and 2, CHCHD3, and CHCHD6, immunocaptured by a mitofilin monoclonal antibody, suggesting a role in protein import or maintenance of mitochondrial structure.\",\n      \"method\": \"Immunoprecipitation (monoclonal antibody immunocapture) followed by protein identification\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying complex members, single study\",\n      \"pmids\": [\"17624330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DNAJC11 localizes to the periphery of the mitochondrial outer membrane (full-length 63 kDa isoform), with putative additional isoforms showing differential submitochondrial localization; it is assembled in a high molecular weight complex similarly to mitofilin; downregulation of mitofilin or SAM50 reduces DNAJC11 protein levels, indicating DNAJC11 stability depends on MICOS complex members.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, western blotting after siRNA knockdown of mitofilin and SAM50 in HeLa cells; rescue experiments with human DNAJC11 overexpression in mutant mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, protein-level dependency, genetic rescue), single lab but comprehensive\",\n      \"pmids\": [\"25111180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss-of-function (splice-site hypomorphic mutation) of DNAJC11 in mice causes motor neuron vacuolation arising from mitochondria with disorganized inner membrane cristae, as well as lymphoid abnormalities, establishing DNAJC11 as required for mitochondrial inner membrane organization in neurons.\",\n      \"method\": \"ENU forward genetics screen, neuropathological analysis (electron microscopy of motor neurons), genetic rescue with human DNAJC11 overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype confirmed by genetic rescue, EM-level resolution\",\n      \"pmids\": [\"25111180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNAJC11 interacts with MICOS complex members (confirming cristae organization role), VDACs at the outer mitochondrial membrane, ribosomal subunits and Hsp70 chaperones in metabolically active cells (HEK293FT), and synaptic proteins in mouse cerebrum; the DUF3395 domain mediates protein-protein interactions while the J-domain determines mitochondrial localization.\",\n      \"method\": \"Affinity purification–mass spectrometry (DNAJC11-FLAG immunoprecipitation) in HEK293FT cells and transgenic mice; domain deletion/mutation analysis\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based interactome in two biological systems with domain-level mechanistic dissection\",\n      \"pmids\": [\"31550165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC11 facilitates ARMC1 release from mitochondria; disrupting the ARMC1–DNAJC11 interaction leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial distribution defects, placing DNAJC11 as a regulator of ARMC1 mito-cytoplasmic shuttling that tunes steady-state mitochondrial distribution.\",\n      \"method\": \"Co-immunoprecipitation, genetic perturbation (ARMC1 deletion, disruption of DNAJC11–ARMC1 interaction), live-cell imaging of mitochondrial distribution\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional epistasis with imaging readout, single study\",\n      \"pmids\": [\"40203102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC11 interacts with SARS-CoV-2 NSP3, stabilizes NSP3 protein through endogenous apoptosis pathways, and facilitates NSP3–NSP4 interaction, thereby promoting double-membrane vesicle (DMV) formation required for viral replication; DNAJC11 knockdown reduces DMV number and size, while DNAJC11 supplementation restores them.\",\n      \"method\": \"Mass spectrometry identification of interaction, co-immunoprecipitation, siRNA knockdown, ectopic overexpression, electron microscopy of DMVs\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MS, Co-IP, KD/OE, EM), single study\",\n      \"pmids\": [\"40872740\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC11 is a mitochondrial outer membrane chaperone-like protein whose J-domain directs mitochondrial localization and whose DUF3395 domain mediates protein–protein interactions; it assembles into the MICOS/MIB supercomplex with mitofilin, SAM50, metaxins, and CHCHD proteins to maintain mitochondrial cristae structure, regulates ARMC1 mito-cytoplasmic shuttling to control mitochondrial distribution, and can stabilize viral NSP3 to promote double-membrane vesicle formation, with loss of function causing cristae disorganization and motor neuron pathology in mice.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DNAJC11 is a mitochondrial outer membrane J-domain protein that maintains mitochondrial cristae architecture and regulates mitochondrial distribution. It assembles into a high-molecular-weight supercomplex with MICOS components (mitofilin, CHCHD3, CHCHD6), SAM50, metaxins, and VDACs, where its DUF3395 domain mediates protein–protein interactions and its J-domain directs mitochondrial localization; its stability depends on mitofilin and SAM50 [PMID:17624330, PMID:25111180, PMID:31550165]. Loss of DNAJC11 in mice causes motor neuron vacuolation with disorganized inner membrane cristae and lymphoid abnormalities, a phenotype rescued by human DNAJC11 overexpression [PMID:25111180]. DNAJC11 also regulates ARMC1 release from mitochondria to tune mitochondrial distribution [PMID:40203102] and can stabilize SARS-CoV-2 NSP3 to promote double-membrane vesicle formation during viral replication [PMID:40872740].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of DNAJC11 as a component of a mitofilin-containing mitochondrial complex with SAM50, metaxins, and CHCHD proteins established that DNAJC11 participates in a multi-subunit assembly at the mitochondrial membranes, raising the question of its specific contribution.\",\n      \"evidence\": \"Immunocapture with mitofilin monoclonal antibody followed by protein identification from mitochondrial extracts\",\n      \"pmids\": [\"17624330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single immunocapture study without reciprocal pull-down from DNAJC11 side\",\n        \"No functional consequence of DNAJC11 loss was tested\",\n        \"Topology and submitochondrial localization of DNAJC11 were undefined\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Determination that DNAJC11 localizes to the mitochondrial outer membrane periphery, depends on mitofilin/SAM50 for stability, and is essential for cristae organization in motor neurons resolved its functional role: DNAJC11 is required for inner membrane architecture, and its loss causes neuronal vacuolation from cristae disorganization.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, siRNA knockdown of mitofilin/SAM50 in HeLa cells; ENU mutagenesis in mice with EM neuropathology and genetic rescue by human DNAJC11 overexpression\",\n      \"pmids\": [\"25111180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which DNAJC11 maintains cristae structure was not defined\",\n        \"Whether the J-domain chaperone activity is enzymatically required was untested\",\n        \"The human disease relevance of DNAJC11 loss-of-function was not established\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systematic interactome mapping and domain dissection revealed that the DUF3395 domain mediates DNAJC11 protein–protein interactions (including MICOS, VDACs, ribosomes, Hsp70) while the J-domain determines mitochondrial targeting, defining the modular logic of DNAJC11 function.\",\n      \"evidence\": \"AP-MS of DNAJC11-FLAG in HEK293FT cells and transgenic mouse cerebrum; domain deletion and mutation analysis\",\n      \"pmids\": [\"31550165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Hsp70 binding reflects active chaperone cycling or passive scaffolding is unknown\",\n        \"Functional significance of ribosomal and synaptic protein interactions was not tested\",\n        \"No structural model of DNAJC11 within the MICOS/MIB supercomplex exists\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that DNAJC11 facilitates ARMC1 release from mitochondria to control mitochondrial distribution expanded its role beyond cristae maintenance to a regulator of organelle positioning.\",\n      \"evidence\": \"Co-IP, genetic perturbation of ARMC1–DNAJC11 interaction, live-cell imaging of mitochondrial distribution\",\n      \"pmids\": [\"40203102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; independent replication is needed\",\n        \"Mechanism by which DNAJC11 releases ARMC1 (chaperone activity vs. competitive binding) is undefined\",\n        \"Relationship between ARMC1-dependent distribution and cristae organization is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DNAJC11 was shown to stabilize SARS-CoV-2 NSP3 and promote NSP3–NSP4 interaction for double-membrane vesicle biogenesis, revealing that its chaperone-like activity can be co-opted during viral infection.\",\n      \"evidence\": \"MS-based interaction identification, Co-IP, siRNA knockdown and overexpression of DNAJC11, EM quantification of DMVs\",\n      \"pmids\": [\"40872740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study on one viral system; breadth of host–pathogen relevance is unknown\",\n        \"Whether J-domain-dependent Hsp70 cycling is required for NSP3 stabilization is untested\",\n        \"Impact on viral replication titers was not reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic contribution of DNAJC11's J-domain chaperone cycle (Hsp70 co-chaperone activity) versus its scaffolding function within the MICOS/MIB supercomplex remains mechanistically unresolved, and no human Mendelian disease has been linked to DNAJC11 mutations.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstitution of DNAJC11 J-domain stimulated ATPase activity with Hsp70 has been performed\",\n        \"No structural data for DNAJC11 or its complexes exist\",\n        \"Human genetic loss-of-function consequences are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [\n      \"MICOS/MIB supercomplex\"\n    ],\n    \"partners\": [\n      \"IMMT\",\n      \"SAMM50\",\n      \"MTX1\",\n      \"MTX2\",\n      \"CHCHD3\",\n      \"CHCHD6\",\n      \"ARMC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}