{"gene":"DNAJC11","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2007,"finding":"DNAJC11 was identified as a component of a mitochondrial complex immunocaptured by anti-mitofilin antibody, co-purifying with mitofilin, metaxins 1 and 2, SAM50, CHCHD3, and CHCHD6, placing DNAJC11 in a mitochondrial inner membrane-associated multi-protein complex.","method":"Monoclonal antibody immunocapture (co-immunoprecipitation) followed by protein identification","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP experiment identifying complex membership, replicated by later independent studies confirming MICOS complex association","pmids":["17624330"],"is_preprint":false},{"year":2014,"finding":"DNAJC11 localizes to the periphery of the mitochondrial outer membrane (full-length 63 kDa isoform), while putative additional isoforms display differential submitochondrial localization. A splice-site hypomorphic mutation in DnaJC11 causes motor neuron vacuolation with mitochondrial inner membrane disorganization and cristae loss in mice, rescued by human DNAJC11 overexpression. DNAJC11 is assembled in a high molecular weight complex similar to mitofilin, and downregulation of mitofilin or SAM50 reduces DNAJC11 protein levels in HeLa cells.","method":"Forward genetics (ENU mutagenesis), subcellular fractionation/localization, rescue by human ortholog overexpression, siRNA knockdown of mitofilin and SAM50 with Western blot, electron microscopy of mitochondrial ultrastructure","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, localization, rescue, epistasis by knockdown), replicated conceptually across labs","pmids":["25111180"],"is_preprint":false},{"year":2019,"finding":"DNAJC11 interacts with members of the MICOS complex, VDACs (outer mitochondrial membrane metabolite channels), ribosomal subunits, and Hsp70 chaperones in HEK293FT cells; in mouse cerebrum it preferentially interacts with synaptic proteins. The DUF3395 domain is critically required for DNAJC11 protein-protein interactions, while the J-domain determines its mitochondrial localization.","method":"FLAG-tag affinity purification followed by mass spectrometry (interactome mapping) in HEK293FT cells and transgenic mice; domain deletion analysis","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative MS-based interactome in two biological systems with domain-function mapping, single lab","pmids":["31550165"],"is_preprint":false},{"year":2015,"finding":"Evolutionary and complexome analyses place DNAJC11 as a peripheral component of the mitochondrial intermembrane space bridging (MIB) complex, specifically in the complete MIB complex form (containing MICOS + SAMM50 + MTX2 + MTX3 + DNAJC11 + MTX1), distinct from the core MICOS complex; its genomic distribution correlates with the presence of mitochondrial cristae across species.","method":"Mitochondrial protein complexome profiling (BN-PAGE/MS) and phylogenomic co-occurrence analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complexome profiling provides direct biochemical evidence for complex membership; evolutionary analysis is correlative but supports functional assignment","pmids":["26477565"],"is_preprint":false},{"year":2025,"finding":"DNAJC11 facilitates release of the mitochondrial distribution regulator ARMC1 from mitochondria; disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial distribution defects, placing DNAJC11 upstream of ARMC1 mito-cytoplasmic shuttling that tunes steady-state mitochondrial distribution.","method":"Co-immunoprecipitation, genetic perturbation (deletion/interaction-disrupting mutants), fluorescence microscopy of mitochondrial distribution","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction and functional rescue experiments in single lab with multiple orthogonal methods","pmids":["40203102"],"is_preprint":false},{"year":2025,"finding":"DNAJC11 interacts with SARS-CoV-2 NSP3, stabilizes NSP3 protein expression through endogenous apoptosis pathways, and facilitates NSP3 interaction with NSP4 to promote double-membrane vesicle (DMV) formation; DNAJC11 knockdown reduces DMV number and size, while DNAJC11 supplementation restores them.","method":"Mass spectrometry identification of interaction, co-immunoprecipitation, siRNA knockdown, ectopic expression, electron microscopy of DMV morphology","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS, Co-IP, KD, OE, EM) in single lab; novel finding not yet independently replicated","pmids":["40872740"],"is_preprint":false},{"year":2017,"finding":"siRNA-mediated silencing of DNAJC11 in mouse podocytes leads to cytoskeletal injury, establishing a functional requirement for DNAJC11 in maintaining podocyte cytoskeletal integrity.","method":"siRNA knockdown with morphological readout of cytoskeletal injury","journal":"Kidney international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA knockdown with phenotypic readout, no molecular pathway placement, single study","pmids":["28709640"],"is_preprint":false}],"current_model":"DNAJC11 is a mitochondrial outer membrane protein whose J-domain directs mitochondrial localization and whose DUF3395 domain mediates protein-protein interactions; it is a peripheral component of the MICOS/MIB complex required for mitochondrial cristae organization, interacts with mitofilin, SAM50, VDACs, Hsp70 chaperones, and synaptic proteins, facilitates ARMC1 release from mitochondria to tune mitochondrial distribution, and loss of DNAJC11 causes mitochondrial inner membrane disorganization and motor neuron pathology in mice."},"narrative":{"mechanistic_narrative":"DNAJC11 is a mitochondrial outer membrane protein that functions as a peripheral component of the mitochondrial intermembrane space bridging (MIB) complex, the extended assembly that joins the core MICOS complex to the SAM50/metaxin machinery and is required for organizing the inner membrane and its cristae [PMID:17624330, PMID:26477565]. It was first identified in a mitofilin-anchored complex alongside SAM50, metaxins 1/2, CHCHD3, and CHCHD6 [PMID:17624330], and its abundance depends on mitofilin and SAM50, consistent with stable incorporation into this complex [PMID:25111180]. Its modular architecture partitions function: the J-domain directs mitochondrial localization while the DUF3395 domain mediates the bulk of its protein-protein interactions, which include MICOS members, the outer-membrane channels VDACs, ribosomal subunits, and Hsp70 chaperones, with a preference for synaptic proteins in neural tissue [PMID:31550165]. Beyond structural roles, DNAJC11 acts upstream of the distribution regulator ARMC1, facilitating ARMC1 release from mitochondria to tune steady-state mitochondrial distribution [PMID:40203102]. Loss of DNAJC11 function in mice causes mitochondrial inner-membrane disorganization, cristae loss, and motor neuron vacuolation that is rescued by the human ortholog [PMID:25111180]. It is also co-opted by SARS-CoV-2, where it stabilizes NSP3 and promotes NSP3–NSP4-driven double-membrane vesicle formation [PMID:40872740].","teleology":[{"year":2007,"claim":"Established DNAJC11 as a physical member of a mitochondrial inner-membrane-associated multiprotein assembly rather than an isolated chaperone, by co-purifying it with the mitofilin/MICOS machinery.","evidence":"Anti-mitofilin monoclonal antibody immunocapture and protein identification","pmids":["17624330"],"confidence":"Medium","gaps":["Single co-IP without domain mapping or reciprocal pulldown","Did not define which subunit DNAJC11 directly contacts","No functional consequence assayed"]},{"year":2014,"claim":"Resolved DNAJC11's submitochondrial position and demonstrated a causal requirement in cristae/inner-membrane architecture, linking its loss to motor neuron pathology.","evidence":"ENU forward genetics, subcellular fractionation, human-ortholog rescue, mitofilin/SAM50 siRNA epistasis, and EM in mice and HeLa cells","pmids":["25111180"],"confidence":"High","gaps":["Mechanism by which a peripheral OMM protein controls inner-membrane organization unresolved","Roles of additional isoforms not defined","J-domain chaperone activity not biochemically tested"]},{"year":2015,"claim":"Distinguished DNAJC11 as a peripheral subunit of the complete MIB complex rather than the core MICOS, and tied its evolutionary presence to cristae-bearing organisms.","evidence":"BN-PAGE/MS complexome profiling and phylogenomic co-occurrence analysis","pmids":["26477565"],"confidence":"Medium","gaps":["Phylogenomic correlation does not prove a cristae-forming function","Stoichiometry and direct binding interface within MIB unresolved"]},{"year":2019,"claim":"Mapped DNAJC11's interactome and assigned domain functions, separating localization (J-domain) from interaction (DUF3395), and revealing tissue-specific partners.","evidence":"FLAG affinity purification–MS in HEK293FT cells and transgenic mouse cerebrum with domain-deletion analysis","pmids":["31550165"],"confidence":"Medium","gaps":["Direct versus indirect interactions not discriminated","Functional consequence of VDAC, ribosomal, and synaptic partner binding not tested","Single-lab interactome"]},{"year":2025,"claim":"Placed DNAJC11 upstream of ARMC1 mito-cytoplasmic shuttling, giving it an active role in tuning mitochondrial distribution beyond structural scaffolding.","evidence":"Co-IP, interaction-disrupting mutants, and fluorescence microscopy of mitochondrial distribution","pmids":["40203102"],"confidence":"Medium","gaps":["Molecular mechanism of ARMC1 release not defined","Single lab; not independently replicated"]},{"year":2025,"claim":"Showed DNAJC11 can be hijacked by SARS-CoV-2 to stabilize NSP3 and support replication-organelle (DMV) biogenesis.","evidence":"MS, co-IP, siRNA knockdown, ectopic expression, and EM of DMV morphology","pmids":["40872740"],"confidence":"Medium","gaps":["Whether this co-opts the normal MIB/cristae function is unknown","Single study, not independently confirmed"]},{"year":null,"claim":"It remains unresolved how a peripheral outer-membrane protein mechanistically drives inner-membrane/cristae organization and whether its J-domain confers genuine co-chaperone activity toward the Hsp70 partners observed.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No demonstrated chaperone/folding activity for the J-domain","Direct binding interface within MIB not structurally defined","Link between cytoskeletal/podocyte phenotype and mitochondrial function unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,3]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,3]}],"complexes":["MICOS complex","MIB complex (mitochondrial intermembrane space bridging)"],"partners":["IMMT (MITOFILIN)","SAMM50","MTX1","MTX2","VDAC","ARMC1","HSPA (HSP70)","NSP3"],"other_free_text":[]}},"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":180,"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":164,"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":11,"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":9126,"output_tokens":1846,"usd":0.027534,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8769,"output_tokens":2434,"usd":0.052347,"stage2_stop_reason":"end_turn"},"total_usd":0.079881,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"DNAJC11 was identified as a component of a mitochondrial complex immunocaptured by anti-mitofilin antibody, co-purifying with mitofilin, metaxins 1 and 2, SAM50, CHCHD3, and CHCHD6, placing DNAJC11 in a mitochondrial inner membrane-associated multi-protein complex.\",\n      \"method\": \"Monoclonal antibody immunocapture (co-immunoprecipitation) followed by protein identification\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP experiment identifying complex membership, replicated by later independent studies confirming MICOS complex association\",\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), while putative additional isoforms display differential submitochondrial localization. A splice-site hypomorphic mutation in DnaJC11 causes motor neuron vacuolation with mitochondrial inner membrane disorganization and cristae loss in mice, rescued by human DNAJC11 overexpression. DNAJC11 is assembled in a high molecular weight complex similar to mitofilin, and downregulation of mitofilin or SAM50 reduces DNAJC11 protein levels in HeLa cells.\",\n      \"method\": \"Forward genetics (ENU mutagenesis), subcellular fractionation/localization, rescue by human ortholog overexpression, siRNA knockdown of mitofilin and SAM50 with Western blot, electron microscopy of mitochondrial ultrastructure\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, localization, rescue, epistasis by knockdown), replicated conceptually across labs\",\n      \"pmids\": [\"25111180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNAJC11 interacts with members of the MICOS complex, VDACs (outer mitochondrial membrane metabolite channels), ribosomal subunits, and Hsp70 chaperones in HEK293FT cells; in mouse cerebrum it preferentially interacts with synaptic proteins. The DUF3395 domain is critically required for DNAJC11 protein-protein interactions, while the J-domain determines its mitochondrial localization.\",\n      \"method\": \"FLAG-tag affinity purification followed by mass spectrometry (interactome mapping) in HEK293FT cells and transgenic mice; domain deletion analysis\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS-based interactome in two biological systems with domain-function mapping, single lab\",\n      \"pmids\": [\"31550165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Evolutionary and complexome analyses place DNAJC11 as a peripheral component of the mitochondrial intermembrane space bridging (MIB) complex, specifically in the complete MIB complex form (containing MICOS + SAMM50 + MTX2 + MTX3 + DNAJC11 + MTX1), distinct from the core MICOS complex; its genomic distribution correlates with the presence of mitochondrial cristae across species.\",\n      \"method\": \"Mitochondrial protein complexome profiling (BN-PAGE/MS) and phylogenomic co-occurrence analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complexome profiling provides direct biochemical evidence for complex membership; evolutionary analysis is correlative but supports functional assignment\",\n      \"pmids\": [\"26477565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC11 facilitates release of the mitochondrial distribution regulator ARMC1 from mitochondria; disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial distribution defects, placing DNAJC11 upstream of ARMC1 mito-cytoplasmic shuttling that tunes steady-state mitochondrial distribution.\",\n      \"method\": \"Co-immunoprecipitation, genetic perturbation (deletion/interaction-disrupting mutants), fluorescence microscopy of mitochondrial distribution\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction and functional rescue experiments in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40203102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC11 interacts with SARS-CoV-2 NSP3, stabilizes NSP3 protein expression through endogenous apoptosis pathways, and facilitates NSP3 interaction with NSP4 to promote double-membrane vesicle (DMV) formation; DNAJC11 knockdown reduces DMV number and size, while DNAJC11 supplementation restores them.\",\n      \"method\": \"Mass spectrometry identification of interaction, co-immunoprecipitation, siRNA knockdown, ectopic expression, electron microscopy of DMV morphology\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS, Co-IP, KD, OE, EM) in single lab; novel finding not yet independently replicated\",\n      \"pmids\": [\"40872740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA-mediated silencing of DNAJC11 in mouse podocytes leads to cytoskeletal injury, establishing a functional requirement for DNAJC11 in maintaining podocyte cytoskeletal integrity.\",\n      \"method\": \"siRNA knockdown with morphological readout of cytoskeletal injury\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA knockdown with phenotypic readout, no molecular pathway placement, single study\",\n      \"pmids\": [\"28709640\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC11 is a mitochondrial outer membrane protein whose J-domain directs mitochondrial localization and whose DUF3395 domain mediates protein-protein interactions; it is a peripheral component of the MICOS/MIB complex required for mitochondrial cristae organization, interacts with mitofilin, SAM50, VDACs, Hsp70 chaperones, and synaptic proteins, facilitates ARMC1 release from mitochondria to tune mitochondrial distribution, and loss of DNAJC11 causes mitochondrial inner membrane disorganization and motor neuron pathology in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAJC11 is a mitochondrial outer membrane protein that functions as a peripheral component of the mitochondrial intermembrane space bridging (MIB) complex, the extended assembly that joins the core MICOS complex to the SAM50/metaxin machinery and is required for organizing the inner membrane and its cristae [#0, #3]. It was first identified in a mitofilin-anchored complex alongside SAM50, metaxins 1/2, CHCHD3, and CHCHD6 [#0], and its abundance depends on mitofilin and SAM50, consistent with stable incorporation into this complex [#1]. Its modular architecture partitions function: the J-domain directs mitochondrial localization while the DUF3395 domain mediates the bulk of its protein-protein interactions, which include MICOS members, the outer-membrane channels VDACs, ribosomal subunits, and Hsp70 chaperones, with a preference for synaptic proteins in neural tissue [#2]. Beyond structural roles, DNAJC11 acts upstream of the distribution regulator ARMC1, facilitating ARMC1 release from mitochondria to tune steady-state mitochondrial distribution [#4]. Loss of DNAJC11 function in mice causes mitochondrial inner-membrane disorganization, cristae loss, and motor neuron vacuolation that is rescued by the human ortholog [#1]. It is also co-opted by SARS-CoV-2, where it stabilizes NSP3 and promotes NSP3–NSP4-driven double-membrane vesicle formation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established DNAJC11 as a physical member of a mitochondrial inner-membrane-associated multiprotein assembly rather than an isolated chaperone, by co-purifying it with the mitofilin/MICOS machinery.\",\n      \"evidence\": \"Anti-mitofilin monoclonal antibody immunocapture and protein identification\",\n      \"pmids\": [\"17624330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without domain mapping or reciprocal pulldown\", \"Did not define which subunit DNAJC11 directly contacts\", \"No functional consequence assayed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved DNAJC11's submitochondrial position and demonstrated a causal requirement in cristae/inner-membrane architecture, linking its loss to motor neuron pathology.\",\n      \"evidence\": \"ENU forward genetics, subcellular fractionation, human-ortholog rescue, mitofilin/SAM50 siRNA epistasis, and EM in mice and HeLa cells\",\n      \"pmids\": [\"25111180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a peripheral OMM protein controls inner-membrane organization unresolved\", \"Roles of additional isoforms not defined\", \"J-domain chaperone activity not biochemically tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Distinguished DNAJC11 as a peripheral subunit of the complete MIB complex rather than the core MICOS, and tied its evolutionary presence to cristae-bearing organisms.\",\n      \"evidence\": \"BN-PAGE/MS complexome profiling and phylogenomic co-occurrence analysis\",\n      \"pmids\": [\"26477565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phylogenomic correlation does not prove a cristae-forming function\", \"Stoichiometry and direct binding interface within MIB unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped DNAJC11's interactome and assigned domain functions, separating localization (J-domain) from interaction (DUF3395), and revealing tissue-specific partners.\",\n      \"evidence\": \"FLAG affinity purification–MS in HEK293FT cells and transgenic mouse cerebrum with domain-deletion analysis\",\n      \"pmids\": [\"31550165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect interactions not discriminated\", \"Functional consequence of VDAC, ribosomal, and synaptic partner binding not tested\", \"Single-lab interactome\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed DNAJC11 upstream of ARMC1 mito-cytoplasmic shuttling, giving it an active role in tuning mitochondrial distribution beyond structural scaffolding.\",\n      \"evidence\": \"Co-IP, interaction-disrupting mutants, and fluorescence microscopy of mitochondrial distribution\",\n      \"pmids\": [\"40203102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of ARMC1 release not defined\", \"Single lab; not independently replicated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed DNAJC11 can be hijacked by SARS-CoV-2 to stabilize NSP3 and support replication-organelle (DMV) biogenesis.\",\n      \"evidence\": \"MS, co-IP, siRNA knockdown, ectopic expression, and EM of DMV morphology\",\n      \"pmids\": [\"40872740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this co-opts the normal MIB/cristae function is unknown\", \"Single study, not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a peripheral outer-membrane protein mechanistically drives inner-membrane/cristae organization and whether its J-domain confers genuine co-chaperone activity toward the Hsp70 partners observed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstrated chaperone/folding activity for the J-domain\", \"Direct binding interface within MIB not structurally defined\", \"Link between cytoskeletal/podocyte phenotype and mitochondrial function unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\n      \"MICOS complex\",\n      \"MIB complex (mitochondrial intermembrane space bridging)\"\n    ],\n    \"partners\": [\n      \"IMMT (mitofilin)\",\n      \"SAMM50\",\n      \"MTX1\",\n      \"MTX2\",\n      \"VDAC\",\n      \"ARMC1\",\n      \"HSPA (Hsp70)\",\n      \"NSP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}