{"gene":"DNAJC15","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2012,"finding":"DNAJC15/MCJ is anchored in the mitochondrial inner membrane with its C-terminal J domain facing the matrix space, where it forms a stable subcomplex with MAGMAS (a component of the mitochondrial import motor) and interacts with core components of the TIM23 pre-protein translocase. The recombinant soluble MCJ domain stimulates the ATPase activity of human mtHsp70 (mortalin), the central component of the TIM23 import motor, and this stimulation is counteracted by MAGMAS. Pre-protein import into mitochondria is impaired in the absence of MCJ.","method":"Subcellular fractionation, co-immunoprecipitation, in vitro ATPase assay with recombinant proteins, yeast complementation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including in vitro reconstitution of ATPase activity, Co-IP, fractionation, and functional yeast complementation in a single study","pmids":["23263864"],"is_preprint":false},{"year":2013,"finding":"DNAJC15/MCJ localizes at the mitochondrial inner membrane where it interacts preferentially with Complex I of the electron transport chain, impairs the formation of respiratory supercomplexes, and functions as a negative regulator of the respiratory chain. Loss of MCJ leads to increased Complex I activity, mitochondrial membrane potential, and ATP production.","method":"Subcellular fractionation, co-immunoprecipitation, Blue Native PAGE for supercomplex analysis, mitochondrial respiration assays in MCJ-deficient mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, supercomplex analysis, and functional respiration assays with KO mouse model; replicated across multiple subsequent studies","pmids":["23530063"],"is_preprint":false},{"year":2014,"finding":"DNAJC15 regulates mitochondrial permeability transition pore (MPTP) opening through interaction with cyclophilin D (CypD). Overexpression of DNAJC15 promotes MPTP opening and apoptosis upon cisplatin treatment, while knockdown suppresses MPTP activation. DNAJC15 specifically recruits and couples CypD to the mitochondrial permeability transition complex.","method":"Overexpression and knockdown in cancer cell lines, co-immunoprecipitation with CypD, MPTP opening assays, apoptosis assays with cisplatin","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP with CypD and functional assays in single lab study","pmids":["24603329"],"is_preprint":false},{"year":2016,"finding":"MCJ acts as an endogenous brake for mitochondrial respiration in CD8+ T cells by interfering with the formation of electron transport chain respiratory supercomplexes. MCJ deficiency increases oxidative phosphorylation and subcellular ATP accumulation, which selectively increases secretion (but not expression) of interferon-γ.","method":"MCJ-deficient mouse model, metabolic profiling (Seahorse), supercomplex analysis, intracellular ATP measurement, IFN-γ secretion assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with metabolic profiling and multiple functional readouts; published in high-impact journal","pmids":["27234056"],"is_preprint":false},{"year":2017,"finding":"APAP (acetaminophen) interferes with the formation of mitochondrial respiratory supercomplexes via MCJ, leading to decreased ATP production and increased ROS generation. MCJ levels are elevated in the liver of patients with acetaminophen overdose.","method":"Blue Native PAGE for supercomplex analysis, ATP measurement, ROS assays, in vivo siRNA inhibition of MCJ in mouse APAP model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway placement with supercomplex analysis, functional assays, and in vivo rescue experiment","pmids":["29233977"],"is_preprint":false},{"year":2018,"finding":"ETV7, a transcriptional repressor, binds the DNAJC15 promoter and represses DNAJC15 expression in response to doxorubicin treatment in breast cancer cells. This ETV7-mediated DNAJC15 repression leads to increased doxorubicin efflux via nuclear pumps, contributing to chemoresistance. DNA methylation may be an additional factor in ETV7-mediated repression.","method":"Chromatin immunoprecipitation (ChIP) identifying ETV7 binding site in DNAJC15 promoter, reporter assays, doxorubicin efflux assays, DNAJC15 rescue experiments","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP identifies direct promoter binding; functional rescue supports pathway placement; single lab study","pmids":["30025229"],"is_preprint":false},{"year":2019,"finding":"In CD8+ T cells, induction of glycolysis upregulates MCJ expression. MCJ acts synergistically with glycolysis to promote caspase-3 activity. MCJ-deficient effector CD8+ T cells exhibit reduced glycolysis and considerably less active caspase-3. In non-glycolytic CD8+ T cells cultured with IL-15, MCJ expression is repressed by methylation, correlating with reduced caspase-3 activity and increased survival.","method":"MCJ-deficient mouse model, glycolysis measurement, active caspase-3 flow cytometry, methylation analysis in IL-15 vs IL-2 cultured T cells","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype and methylation mechanism; single lab","pmids":["30915331"],"is_preprint":false},{"year":2020,"finding":"Therapeutic silencing of MCJ in the liver using nanoparticle- and GalNAc-formulated siRNA reduces liver lipid accumulation and fibrosis in NASH mouse models by enhancing hepatocyte β-oxidation of fatty acids and increasing mitochondrial respiration.","method":"siRNA knockdown in vivo, fatty acid β-oxidation assays, histological assessment of lipid and fibrosis, multiple NASH mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo models with mechanistic assays; replicated across different formulations","pmids":["32620763"],"is_preprint":false},{"year":2004,"finding":"Cell type-specific expression of DNAJC15/MCJ is controlled by methylation of a CpG island within its first exon (not promoter). In epithelial cells, this CpG island is methylated and the gene is silenced; in lymphocyte or fibroblast cells, it is unmethylated and expressed. CpG island methylation is associated with loss of histone acetylation not only at the island but also at the promoter region, suggesting CpG methylation directs chromatin remodeling to silence the gene.","method":"Bisulfite sequencing, RT-PCR expression analysis across cell types, chromatin immunoprecipitation (ChIP) for histone acetylation","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP combined with bisulfite sequencing across multiple cell types; single lab","pmids":["14729589"],"is_preprint":false},{"year":2024,"finding":"S-adenosylmethionine (SAMe) negatively regulates MCJ expression in the liver. MCJ is methylated at lysine residues and interacts with methionine adenosyltransferase alpha 1 (MATα1) in liver mitochondria, likely to facilitate its methylation. Deficiency of MATα1 leads to hepatic MCJ upregulation, while MAT1A overexpression and SAMe treatment reduce MCJ expression.","method":"Co-immunoprecipitation of MCJ with MATα1, mass spectrometry identification of lysine methylation, MAT1A overexpression and SAMe treatment in mouse models, MCJ-KO mouse","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, mass spectrometry for PTM identification, and in vivo genetic/pharmacological rescue; single lab","pmids":["38385082"],"is_preprint":false},{"year":2025,"finding":"High levels of DNAJC15 in ovarian cancer cells are associated with accumulation of lipid droplets and increased lipid peroxidation, leading to ferroptosis induction. DNAJC15 overexpression promotes sensitivity to cisplatin through ferroptosis; inhibiting lipid peroxidation with Ferrostatin-1 rescues the cisplatin-resistant phenotype, placing DNAJC15 upstream of ferroptosis in modulating chemosensitivity.","method":"DNAJC15 overexpression in ovarian cancer cell lines, lipid peroxidation assays, ferroptosis rescue with Ferrostatin-1, cisplatin sensitivity assays","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — overexpression with pharmacological rescue establishing pathway placement; single lab","pmids":["39809321"],"is_preprint":false},{"year":2025,"finding":"Loss of MCJ/DnaJC15 promotes brown adipose tissue (BAT) thermogenesis through an eIF2α-mediated stress response pathway. MCJKO mice exhibit elevated BAT thermogenesis even without UCP1. In vivo CRISPR deletion of eIF2α in MCJKO mice abrogates thermogenesis, placing eIF2α downstream of MCJ loss in BAT activation. Electron microscopy reveals changes in mitochondrial morphology consistent with BAT activation.","method":"MCJKO mouse model, in vivo CRISPR deletion of eIF2α, electron microscopy, proteomic analysis, thermogenesis measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via in vivo CRISPR with clear phenotypic readout; multiple orthogonal methods","pmids":["39805849"],"is_preprint":false},{"year":2026,"finding":"Under mitochondrial stress, the peptidase OMA1 cleaves DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response.","method":"In vitro cleavage assays with OMA1, protease substrate identification, mitochondrial protein import assays, ER stress/UPR reporter assays, AFG3L2 genetic manipulation","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical cleavage assay, genetic manipulation of OMA1 and AFG3L2, functional import assays with multiple readouts","pmids":["41760807"],"is_preprint":false},{"year":2026,"finding":"Elevated MCJ levels in proliferating cancer cells reroute electron flux from Complex I to succinate dehydrogenase (Complex II), enabling lipid-fueled mitochondrial respiration and suppressing glycolysis. This MCJ-mediated metabolic shift promotes cell proliferation and migration, and increases lipid accumulation and β-oxidation while preserving NADH levels for higher redox potential.","method":"MCJ overexpression/knockdown in cancer cells, Seahorse metabolic flux assays, Complex I/II activity assays, lipid accumulation assays, proliferation and migration assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — overexpression/KD with mechanistic metabolic assays; single lab, single study","pmids":["41484063"],"is_preprint":false}],"current_model":"DNAJC15/MCJ is a mitochondrial inner membrane co-chaperone that negatively regulates Complex I of the electron transport chain by impairing respiratory supercomplex formation, thereby restraining oxidative phosphorylation, ATP production, and mitochondrial membrane potential; it also functions as a J co-chaperone for the TIM23 protein import translocase (stimulating mtHsp70 ATPase activity), regulates mitochondrial permeability transition through cyclophilin D, is subject to OMA1-mediated cleavage and AFG3L2-dependent degradation under stress, is regulated by SAMe-dependent lysine methylation via MATα1, and its expression is epigenetically controlled by CpG island methylation, with transcriptional repression also mediated by the ETV7 repressor."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that DNAJC15 expression is controlled by an unusual epigenetic switch — CpG methylation within its first exon rather than the promoter — explained why the gene is silenced in epithelial cells but active in lymphocytes and fibroblasts.","evidence":"Bisulfite sequencing and ChIP for histone acetylation across multiple human cell types","pmids":["14729589"],"confidence":"Medium","gaps":["Writers and erasers of this CpG methylation mark were not identified","Whether methylation-dependent silencing is causal for cancer chemoresistance was not tested"]},{"year":2012,"claim":"Defining DNAJC15 as a mitochondrial inner membrane J co-chaperone of the TIM23 translocase resolved its molecular function: the matrix-facing J domain stimulates mtHsp70 ATPase activity, and MAGMAS antagonizes this stimulation, establishing a regulatory pair within the import motor.","evidence":"Subcellular fractionation, Co-IP with TIM23 components, in vitro ATPase assay with recombinant proteins, yeast complementation","pmids":["23263864"],"confidence":"High","gaps":["Structural basis of DNAJC15–MAGMAS antagonism on mtHsp70 was not resolved","Relative contributions of DNAJC15 versus other J proteins to TIM23-dependent import remain unclear"]},{"year":2013,"claim":"Demonstrating that DNAJC15 interacts with Complex I and impairs respiratory supercomplex assembly revealed a second, distinct function as an endogenous negative regulator of the electron transport chain, beyond its role in protein import.","evidence":"Co-IP with Complex I, Blue Native PAGE supercomplex analysis, respiration assays in MCJ-KO mice","pmids":["23530063"],"confidence":"High","gaps":["Molecular mechanism by which DNAJC15 destabilizes supercomplexes (direct steric block vs. chaperone activity) was not determined","Whether Complex I regulation and TIM23 import functions are independent or coupled was not addressed"]},{"year":2014,"claim":"Showing that DNAJC15 interacts with cyclophilin D to promote mitochondrial permeability transition pore opening linked its respiratory regulation to apoptotic sensitivity upon cisplatin treatment.","evidence":"Co-IP with CypD, MPTP opening and apoptosis assays with overexpression/knockdown in cancer cell lines","pmids":["24603329"],"confidence":"Medium","gaps":["Whether DNAJC15 acts on CypD through its J-domain chaperone activity or a distinct mechanism is unknown","Interaction with CypD has not been independently confirmed by a second group"]},{"year":2016,"claim":"Extending the supercomplex-brake model to CD8+ T cell immunometabolism showed that MCJ restrains oxidative phosphorylation to limit ATP-dependent IFN-γ secretion, establishing a physiological role for this metabolic checkpoint in adaptive immunity.","evidence":"MCJ-KO mice, Seahorse metabolic profiling, supercomplex analysis, intracellular ATP and IFN-γ secretion assays","pmids":["27234056"],"confidence":"High","gaps":["Whether MCJ regulation of T cell effector function extends to other cytokines or cytotoxic granules was not tested","Signal controlling MCJ downregulation during memory T cell formation was not fully defined"]},{"year":2017,"claim":"Identifying MCJ as a mediator of acetaminophen hepatotoxicity — APAP elevates MCJ and disrupts supercomplexes, while MCJ silencing rescues ATP and reduces ROS — demonstrated therapeutic relevance of the Complex I brake in drug-induced liver injury.","evidence":"Blue Native PAGE, ATP/ROS assays, in vivo siRNA in APAP mouse model, human liver samples from overdose patients","pmids":["29233977"],"confidence":"High","gaps":["Mechanism by which APAP upregulates MCJ protein levels was not determined","Long-term effects of MCJ silencing on liver homeostasis were not assessed"]},{"year":2018,"claim":"Identifying ETV7 as a transcriptional repressor that directly binds the DNAJC15 promoter provided a mechanism for doxorubicin-induced DNAJC15 silencing and consequent chemoresistance in breast cancer.","evidence":"ChIP for ETV7 at DNAJC15 promoter, reporter assays, doxorubicin efflux and rescue experiments","pmids":["30025229"],"confidence":"Medium","gaps":["Whether ETV7-mediated repression operates in cancer types beyond breast cancer is unknown","Mechanism linking DNAJC15 loss to increased drug efflux pump activity remains indirect"]},{"year":2019,"claim":"Linking glycolysis-driven MCJ induction to caspase-3 activation in effector CD8+ T cells, and methylation-dependent MCJ silencing with IL-15-mediated survival, revealed that metabolic reprogramming toggles MCJ expression to control T cell fate.","evidence":"MCJ-KO mice, glycolysis measurement, active caspase-3 flow cytometry, methylation analysis in IL-15 vs. IL-2 cultured T cells","pmids":["30915331"],"confidence":"Medium","gaps":["Methyltransferase responsible for MCJ silencing in IL-15 conditions was not identified","Whether MCJ-driven caspase-3 activation is via MPTP or a separate pathway was not resolved"]},{"year":2020,"claim":"Therapeutic siRNA silencing of MCJ in NASH mouse models reduced steatosis and fibrosis by enhancing hepatocyte β-oxidation, providing preclinical proof-of-concept that releasing the MCJ brake on mitochondrial respiration can treat metabolic liver disease.","evidence":"Nanoparticle- and GalNAc-formulated siRNA in vivo, β-oxidation assays, histology across multiple NASH models","pmids":["32620763"],"confidence":"High","gaps":["Whether chronic MCJ silencing causes compensatory metabolic reprogramming or ROS toxicity was not examined long-term","Applicability to human NASH was not demonstrated"]},{"year":2024,"claim":"Discovering that MATα1 localizes to liver mitochondria, interacts with MCJ, and facilitates SAMe-dependent lysine methylation that reduces MCJ levels introduced a novel post-translational mechanism controlling the abundance of the Complex I brake.","evidence":"Co-IP of MCJ with MATα1, mass spectrometry of lysine methylation, MAT1A overexpression and SAMe treatment in mice","pmids":["38385082"],"confidence":"Medium","gaps":["How lysine methylation leads to reduced MCJ protein (degradation vs. altered stability) is not defined","Specific lysine residue(s) critical for regulation were not mutated to confirm functional relevance"]},{"year":2025,"claim":"Two studies expanded DNAJC15's physiological reach: loss of MCJ activates BAT thermogenesis via an eIF2α stress pathway even without UCP1, and DNAJC15 overexpression in ovarian cancer promotes lipid peroxidation-driven ferroptosis that sensitizes cells to cisplatin.","evidence":"MCJKO mice with in vivo CRISPR deletion of eIF2α for epistasis; DNAJC15 overexpression in ovarian cancer lines with ferroptosis rescue by Ferrostatin-1","pmids":["39805849","39809321"],"confidence":"High","gaps":["Whether MCJ-dependent eIF2α activation is a direct signaling event or secondary to mitochondrial stress is unclear","Ferroptosis link derives from overexpression; relevance at endogenous MCJ levels in ovarian cancer is unconfirmed"]},{"year":2026,"claim":"Two mechanistic advances clarified MCJ's stress-responsive regulation and metabolic rewiring: OMA1 cleaves DNAJC15 during mitochondrial stress to restrict TIM23 import and OXPHOS biogenesis (triggering ER UPR via mislocalized preproteins), and elevated MCJ in cancer cells reroutes electron flux from Complex I to Complex II to support lipid-fueled respiration.","evidence":"In vitro OMA1 cleavage assays, AFG3L2 genetic manipulation, import assays, UPR reporters; Seahorse flux and Complex I/II activity assays with MCJ overexpression/knockdown in cancer cells","pmids":["41760807","41484063"],"confidence":"High","gaps":["Structure of the OMA1-DNAJC15 cleavage complex and site specificity are not resolved","Whether Complex I-to-II electron rerouting requires DNAJC15's J-domain chaperone activity or a scaffolding role is unknown","Integration of OMA1-mediated degradation with MATα1-dependent methylation in controlling MCJ levels has not been examined"]},{"year":null,"claim":"A unified structural and mechanistic model explaining how DNAJC15 simultaneously regulates TIM23-dependent protein import and Complex I supercomplex stability — and how these two functions are coordinated under normal versus stress conditions — remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of DNAJC15 in complex with either TIM23 or Complex I exists","Whether import and supercomplex functions are mediated by the same or distinct DNAJC15 pools is unknown","Relative contribution of OMA1 cleavage vs. MATα1-dependent methylation in setting MCJ steady-state levels in different tissues is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,12]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,3,9,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3,4,7,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,6,10]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,11,12]}],"complexes":["TIM23 translocase","Complex I (NADH:ubiquinone oxidoreductase)"],"partners":["MAGMAS","HSPA9","PPIF","OMA1","AFG3L2","MAT1A","ETV7"],"other_free_text":[]},"mechanistic_narrative":"DNAJC15 (MCJ) is a mitochondrial inner membrane co-chaperone that functions as a central regulator of electron transport chain activity and mitochondrial protein import. It negatively regulates Complex I by impairing respiratory supercomplex formation, thereby restraining oxidative phosphorylation, ATP production, and mitochondrial membrane potential; loss of MCJ enhances Complex I activity, fatty acid β-oxidation, and thermogenesis across multiple tissues including liver, CD8+ T cells, and brown adipose tissue [PMID:23530063, PMID:27234056, PMID:32620763, PMID:39805849]. As a J-domain protein anchored with its C-terminal J domain facing the matrix, DNAJC15 stimulates mtHsp70 ATPase activity within the TIM23 import motor and is essential for efficient mitochondrial pre-protein import; under stress, OMA1 cleaves DNAJC15 to restrict import and OXPHOS biogenesis, coupling mitochondrial fitness to import capacity [PMID:23263864, PMID:41760807]. DNAJC15 expression is epigenetically regulated by CpG island methylation within its first exon and by the transcriptional repressor ETV7, and post-translationally by MATα1-dependent lysine methylation, providing multilayered control over its metabolic brake function [PMID:14729589, PMID:30025229, PMID:38385082]."},"prefetch_data":{"uniprot":{"accession":"Q9Y5T4","full_name":"DnaJ homolog subfamily C member 15","aliases":["Cell growth-inhibiting gene 22 protein","Methylation-controlled J protein","MCJ"],"length_aa":150,"mass_kda":16.4,"function":"Negative regulator of the mitochondrial respiratory chain. Prevents mitochondrial hyperpolarization state and restricts mitochondrial generation of ATP (By similarity). Acts as an import component of the TIM23 translocase complex. Stimulates the ATPase activity of HSPA9","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y5T4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJC15","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/DNAJC15","total_profiled":1310},"omim":[{"mim_id":"615339","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 15; DNAJC15","url":"https://www.omim.org/entry/615339"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNAJC15"},"hgnc":{"alias_symbol":["MCJ"],"prev_symbol":["DNAJD1"]},"alphafold":{"accession":"Q9Y5T4","domains":[{"cath_id":"1.10.287.110","chopping":"95-148","consensus_level":"high","plddt":96.1309,"start":95,"end":148},{"cath_id":"1.20.5","chopping":"35-77","consensus_level":"medium","plddt":77.9133,"start":35,"end":77}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5T4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5T4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5T4-F1-predicted_aligned_error_v6.png","plddt_mean":78.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAJC15","jax_strain_url":"https://www.jax.org/strain/search?query=DNAJC15"},"sequence":{"accession":"Q9Y5T4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5T4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5T4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5T4"}},"corpus_meta":[{"pmid":"32620763","id":"PMC_32620763","title":"Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32620763","citation_count":110,"is_preprint":false},{"pmid":"23530063","id":"PMC_23530063","title":"MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23530063","citation_count":100,"is_preprint":false},{"pmid":"29233977","id":"PMC_29233977","title":"The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29233977","citation_count":95,"is_preprint":false},{"pmid":"27234056","id":"PMC_27234056","title":"Fine-Tuning of CD8(+) T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus.","date":"2016","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/27234056","citation_count":62,"is_preprint":false},{"pmid":"14729589","id":"PMC_14729589","title":"Cell type-specific methylation of an intronic CpG island controls expression of the MCJ gene.","date":"2004","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/14729589","citation_count":58,"is_preprint":false},{"pmid":"15894365","id":"PMC_15894365","title":"Demethylation of the MCJ gene in stage III/IV epithelial ovarian cancer and response to chemotherapy.","date":"2005","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15894365","citation_count":56,"is_preprint":false},{"pmid":"16049974","id":"PMC_16049974","title":"Epigenetic inactivation of MCJ (DNAJD1) in malignant paediatric brain tumours.","date":"2006","source":"International journal of 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/38971734","citation_count":2,"is_preprint":false},{"pmid":"40907687","id":"PMC_40907687","title":"MicroRNA-29a attenuates inflammation and fibrosis in an animal model of NASH through MCJ inhibition and hippo pathway regulation.","date":"2025","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40907687","citation_count":1,"is_preprint":false},{"pmid":"36978641","id":"PMC_36978641","title":"In Vivo and In Vitro Expression of iC1, a Methylation-Controlled J Protein (MCJ) in Bovine Liver, and Response to In Vitro Bovine Fatty Liver Disease Model.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36978641","citation_count":1,"is_preprint":false},{"pmid":"41760807","id":"PMC_41760807","title":"Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.","date":"2026","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41760807","citation_count":0,"is_preprint":false},{"pmid":"34495814","id":"PMC_34495814","title":"The in vitro antiviral activity of Lacticaseibacillus casei MCJ protein-based metabolites on bovine viral diarrhea virus.","date":"2021","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34495814","citation_count":0,"is_preprint":false},{"pmid":"35306115","id":"PMC_35306115","title":"Polyploidization affects the allelic variation of jasmonate-regulated protein Ta-JA1 belonging to the monocot chimeric jacalin (MCJ) family in wild emmer wheat.","date":"2022","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/35306115","citation_count":0,"is_preprint":false},{"pmid":"41484063","id":"PMC_41484063","title":"MCJ modulates mitochondrial ETC flux to promote lipid metabolism-driven enhancement of cell proliferation and migration.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41484063","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14533,"output_tokens":3620,"usd":0.048949},"stage2":{"model":"claude-opus-4-6","input_tokens":7061,"output_tokens":3527,"usd":0.18522},"total_usd":0.234169,"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\": 2012,\n      \"finding\": \"DNAJC15/MCJ is anchored in the mitochondrial inner membrane with its C-terminal J domain facing the matrix space, where it forms a stable subcomplex with MAGMAS (a component of the mitochondrial import motor) and interacts with core components of the TIM23 pre-protein translocase. The recombinant soluble MCJ domain stimulates the ATPase activity of human mtHsp70 (mortalin), the central component of the TIM23 import motor, and this stimulation is counteracted by MAGMAS. Pre-protein import into mitochondria is impaired in the absence of MCJ.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, in vitro ATPase assay with recombinant proteins, yeast complementation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including in vitro reconstitution of ATPase activity, Co-IP, fractionation, and functional yeast complementation in a single study\",\n      \"pmids\": [\"23263864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DNAJC15/MCJ localizes at the mitochondrial inner membrane where it interacts preferentially with Complex I of the electron transport chain, impairs the formation of respiratory supercomplexes, and functions as a negative regulator of the respiratory chain. Loss of MCJ leads to increased Complex I activity, mitochondrial membrane potential, and ATP production.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, Blue Native PAGE for supercomplex analysis, mitochondrial respiration assays in MCJ-deficient mice\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, supercomplex analysis, and functional respiration assays with KO mouse model; replicated across multiple subsequent studies\",\n      \"pmids\": [\"23530063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DNAJC15 regulates mitochondrial permeability transition pore (MPTP) opening through interaction with cyclophilin D (CypD). Overexpression of DNAJC15 promotes MPTP opening and apoptosis upon cisplatin treatment, while knockdown suppresses MPTP activation. DNAJC15 specifically recruits and couples CypD to the mitochondrial permeability transition complex.\",\n      \"method\": \"Overexpression and knockdown in cancer cell lines, co-immunoprecipitation with CypD, MPTP opening assays, apoptosis assays with cisplatin\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP with CypD and functional assays in single lab study\",\n      \"pmids\": [\"24603329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MCJ acts as an endogenous brake for mitochondrial respiration in CD8+ T cells by interfering with the formation of electron transport chain respiratory supercomplexes. MCJ deficiency increases oxidative phosphorylation and subcellular ATP accumulation, which selectively increases secretion (but not expression) of interferon-γ.\",\n      \"method\": \"MCJ-deficient mouse model, metabolic profiling (Seahorse), supercomplex analysis, intracellular ATP measurement, IFN-γ secretion assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with metabolic profiling and multiple functional readouts; published in high-impact journal\",\n      \"pmids\": [\"27234056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APAP (acetaminophen) interferes with the formation of mitochondrial respiratory supercomplexes via MCJ, leading to decreased ATP production and increased ROS generation. MCJ levels are elevated in the liver of patients with acetaminophen overdose.\",\n      \"method\": \"Blue Native PAGE for supercomplex analysis, ATP measurement, ROS assays, in vivo siRNA inhibition of MCJ in mouse APAP model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement with supercomplex analysis, functional assays, and in vivo rescue experiment\",\n      \"pmids\": [\"29233977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ETV7, a transcriptional repressor, binds the DNAJC15 promoter and represses DNAJC15 expression in response to doxorubicin treatment in breast cancer cells. This ETV7-mediated DNAJC15 repression leads to increased doxorubicin efflux via nuclear pumps, contributing to chemoresistance. DNA methylation may be an additional factor in ETV7-mediated repression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) identifying ETV7 binding site in DNAJC15 promoter, reporter assays, doxorubicin efflux assays, DNAJC15 rescue experiments\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP identifies direct promoter binding; functional rescue supports pathway placement; single lab study\",\n      \"pmids\": [\"30025229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In CD8+ T cells, induction of glycolysis upregulates MCJ expression. MCJ acts synergistically with glycolysis to promote caspase-3 activity. MCJ-deficient effector CD8+ T cells exhibit reduced glycolysis and considerably less active caspase-3. In non-glycolytic CD8+ T cells cultured with IL-15, MCJ expression is repressed by methylation, correlating with reduced caspase-3 activity and increased survival.\",\n      \"method\": \"MCJ-deficient mouse model, glycolysis measurement, active caspase-3 flow cytometry, methylation analysis in IL-15 vs IL-2 cultured T cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype and methylation mechanism; single lab\",\n      \"pmids\": [\"30915331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Therapeutic silencing of MCJ in the liver using nanoparticle- and GalNAc-formulated siRNA reduces liver lipid accumulation and fibrosis in NASH mouse models by enhancing hepatocyte β-oxidation of fatty acids and increasing mitochondrial respiration.\",\n      \"method\": \"siRNA knockdown in vivo, fatty acid β-oxidation assays, histological assessment of lipid and fibrosis, multiple NASH mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo models with mechanistic assays; replicated across different formulations\",\n      \"pmids\": [\"32620763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cell type-specific expression of DNAJC15/MCJ is controlled by methylation of a CpG island within its first exon (not promoter). In epithelial cells, this CpG island is methylated and the gene is silenced; in lymphocyte or fibroblast cells, it is unmethylated and expressed. CpG island methylation is associated with loss of histone acetylation not only at the island but also at the promoter region, suggesting CpG methylation directs chromatin remodeling to silence the gene.\",\n      \"method\": \"Bisulfite sequencing, RT-PCR expression analysis across cell types, chromatin immunoprecipitation (ChIP) for histone acetylation\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP combined with bisulfite sequencing across multiple cell types; single lab\",\n      \"pmids\": [\"14729589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"S-adenosylmethionine (SAMe) negatively regulates MCJ expression in the liver. MCJ is methylated at lysine residues and interacts with methionine adenosyltransferase alpha 1 (MATα1) in liver mitochondria, likely to facilitate its methylation. Deficiency of MATα1 leads to hepatic MCJ upregulation, while MAT1A overexpression and SAMe treatment reduce MCJ expression.\",\n      \"method\": \"Co-immunoprecipitation of MCJ with MATα1, mass spectrometry identification of lysine methylation, MAT1A overexpression and SAMe treatment in mouse models, MCJ-KO mouse\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, mass spectrometry for PTM identification, and in vivo genetic/pharmacological rescue; single lab\",\n      \"pmids\": [\"38385082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"High levels of DNAJC15 in ovarian cancer cells are associated with accumulation of lipid droplets and increased lipid peroxidation, leading to ferroptosis induction. DNAJC15 overexpression promotes sensitivity to cisplatin through ferroptosis; inhibiting lipid peroxidation with Ferrostatin-1 rescues the cisplatin-resistant phenotype, placing DNAJC15 upstream of ferroptosis in modulating chemosensitivity.\",\n      \"method\": \"DNAJC15 overexpression in ovarian cancer cell lines, lipid peroxidation assays, ferroptosis rescue with Ferrostatin-1, cisplatin sensitivity assays\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — overexpression with pharmacological rescue establishing pathway placement; single lab\",\n      \"pmids\": [\"39809321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of MCJ/DnaJC15 promotes brown adipose tissue (BAT) thermogenesis through an eIF2α-mediated stress response pathway. MCJKO mice exhibit elevated BAT thermogenesis even without UCP1. In vivo CRISPR deletion of eIF2α in MCJKO mice abrogates thermogenesis, placing eIF2α downstream of MCJ loss in BAT activation. Electron microscopy reveals changes in mitochondrial morphology consistent with BAT activation.\",\n      \"method\": \"MCJKO mouse model, in vivo CRISPR deletion of eIF2α, electron microscopy, proteomic analysis, thermogenesis measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via in vivo CRISPR with clear phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"39805849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Under mitochondrial stress, the peptidase OMA1 cleaves DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response.\",\n      \"method\": \"In vitro cleavage assays with OMA1, protease substrate identification, mitochondrial protein import assays, ER stress/UPR reporter assays, AFG3L2 genetic manipulation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical cleavage assay, genetic manipulation of OMA1 and AFG3L2, functional import assays with multiple readouts\",\n      \"pmids\": [\"41760807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Elevated MCJ levels in proliferating cancer cells reroute electron flux from Complex I to succinate dehydrogenase (Complex II), enabling lipid-fueled mitochondrial respiration and suppressing glycolysis. This MCJ-mediated metabolic shift promotes cell proliferation and migration, and increases lipid accumulation and β-oxidation while preserving NADH levels for higher redox potential.\",\n      \"method\": \"MCJ overexpression/knockdown in cancer cells, Seahorse metabolic flux assays, Complex I/II activity assays, lipid accumulation assays, proliferation and migration assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — overexpression/KD with mechanistic metabolic assays; single lab, single study\",\n      \"pmids\": [\"41484063\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC15/MCJ is a mitochondrial inner membrane co-chaperone that negatively regulates Complex I of the electron transport chain by impairing respiratory supercomplex formation, thereby restraining oxidative phosphorylation, ATP production, and mitochondrial membrane potential; it also functions as a J co-chaperone for the TIM23 protein import translocase (stimulating mtHsp70 ATPase activity), regulates mitochondrial permeability transition through cyclophilin D, is subject to OMA1-mediated cleavage and AFG3L2-dependent degradation under stress, is regulated by SAMe-dependent lysine methylation via MATα1, and its expression is epigenetically controlled by CpG island methylation, with transcriptional repression also mediated by the ETV7 repressor.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DNAJC15 (MCJ) is a mitochondrial inner membrane co-chaperone that functions as a central regulator of electron transport chain activity and mitochondrial protein import. It negatively regulates Complex I by impairing respiratory supercomplex formation, thereby restraining oxidative phosphorylation, ATP production, and mitochondrial membrane potential; loss of MCJ enhances Complex I activity, fatty acid β-oxidation, and thermogenesis across multiple tissues including liver, CD8+ T cells, and brown adipose tissue [PMID:23530063, PMID:27234056, PMID:32620763, PMID:39805849]. As a J-domain protein anchored with its C-terminal J domain facing the matrix, DNAJC15 stimulates mtHsp70 ATPase activity within the TIM23 import motor and is essential for efficient mitochondrial pre-protein import; under stress, OMA1 cleaves DNAJC15 to restrict import and OXPHOS biogenesis, coupling mitochondrial fitness to import capacity [PMID:23263864, PMID:41760807]. DNAJC15 expression is epigenetically regulated by CpG island methylation within its first exon and by the transcriptional repressor ETV7, and post-translationally by MATα1-dependent lysine methylation, providing multilayered control over its metabolic brake function [PMID:14729589, PMID:30025229, PMID:38385082].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that DNAJC15 expression is controlled by an unusual epigenetic switch — CpG methylation within its first exon rather than the promoter — explained why the gene is silenced in epithelial cells but active in lymphocytes and fibroblasts.\",\n      \"evidence\": \"Bisulfite sequencing and ChIP for histone acetylation across multiple human cell types\",\n      \"pmids\": [\"14729589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Writers and erasers of this CpG methylation mark were not identified\",\n        \"Whether methylation-dependent silencing is causal for cancer chemoresistance was not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining DNAJC15 as a mitochondrial inner membrane J co-chaperone of the TIM23 translocase resolved its molecular function: the matrix-facing J domain stimulates mtHsp70 ATPase activity, and MAGMAS antagonizes this stimulation, establishing a regulatory pair within the import motor.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP with TIM23 components, in vitro ATPase assay with recombinant proteins, yeast complementation\",\n      \"pmids\": [\"23263864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of DNAJC15–MAGMAS antagonism on mtHsp70 was not resolved\",\n        \"Relative contributions of DNAJC15 versus other J proteins to TIM23-dependent import remain unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that DNAJC15 interacts with Complex I and impairs respiratory supercomplex assembly revealed a second, distinct function as an endogenous negative regulator of the electron transport chain, beyond its role in protein import.\",\n      \"evidence\": \"Co-IP with Complex I, Blue Native PAGE supercomplex analysis, respiration assays in MCJ-KO mice\",\n      \"pmids\": [\"23530063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which DNAJC15 destabilizes supercomplexes (direct steric block vs. chaperone activity) was not determined\",\n        \"Whether Complex I regulation and TIM23 import functions are independent or coupled was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that DNAJC15 interacts with cyclophilin D to promote mitochondrial permeability transition pore opening linked its respiratory regulation to apoptotic sensitivity upon cisplatin treatment.\",\n      \"evidence\": \"Co-IP with CypD, MPTP opening and apoptosis assays with overexpression/knockdown in cancer cell lines\",\n      \"pmids\": [\"24603329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DNAJC15 acts on CypD through its J-domain chaperone activity or a distinct mechanism is unknown\",\n        \"Interaction with CypD has not been independently confirmed by a second group\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extending the supercomplex-brake model to CD8+ T cell immunometabolism showed that MCJ restrains oxidative phosphorylation to limit ATP-dependent IFN-γ secretion, establishing a physiological role for this metabolic checkpoint in adaptive immunity.\",\n      \"evidence\": \"MCJ-KO mice, Seahorse metabolic profiling, supercomplex analysis, intracellular ATP and IFN-γ secretion assays\",\n      \"pmids\": [\"27234056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MCJ regulation of T cell effector function extends to other cytokines or cytotoxic granules was not tested\",\n        \"Signal controlling MCJ downregulation during memory T cell formation was not fully defined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying MCJ as a mediator of acetaminophen hepatotoxicity — APAP elevates MCJ and disrupts supercomplexes, while MCJ silencing rescues ATP and reduces ROS — demonstrated therapeutic relevance of the Complex I brake in drug-induced liver injury.\",\n      \"evidence\": \"Blue Native PAGE, ATP/ROS assays, in vivo siRNA in APAP mouse model, human liver samples from overdose patients\",\n      \"pmids\": [\"29233977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which APAP upregulates MCJ protein levels was not determined\",\n        \"Long-term effects of MCJ silencing on liver homeostasis were not assessed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying ETV7 as a transcriptional repressor that directly binds the DNAJC15 promoter provided a mechanism for doxorubicin-induced DNAJC15 silencing and consequent chemoresistance in breast cancer.\",\n      \"evidence\": \"ChIP for ETV7 at DNAJC15 promoter, reporter assays, doxorubicin efflux and rescue experiments\",\n      \"pmids\": [\"30025229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ETV7-mediated repression operates in cancer types beyond breast cancer is unknown\",\n        \"Mechanism linking DNAJC15 loss to increased drug efflux pump activity remains indirect\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking glycolysis-driven MCJ induction to caspase-3 activation in effector CD8+ T cells, and methylation-dependent MCJ silencing with IL-15-mediated survival, revealed that metabolic reprogramming toggles MCJ expression to control T cell fate.\",\n      \"evidence\": \"MCJ-KO mice, glycolysis measurement, active caspase-3 flow cytometry, methylation analysis in IL-15 vs. IL-2 cultured T cells\",\n      \"pmids\": [\"30915331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Methyltransferase responsible for MCJ silencing in IL-15 conditions was not identified\",\n        \"Whether MCJ-driven caspase-3 activation is via MPTP or a separate pathway was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Therapeutic siRNA silencing of MCJ in NASH mouse models reduced steatosis and fibrosis by enhancing hepatocyte β-oxidation, providing preclinical proof-of-concept that releasing the MCJ brake on mitochondrial respiration can treat metabolic liver disease.\",\n      \"evidence\": \"Nanoparticle- and GalNAc-formulated siRNA in vivo, β-oxidation assays, histology across multiple NASH models\",\n      \"pmids\": [\"32620763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether chronic MCJ silencing causes compensatory metabolic reprogramming or ROS toxicity was not examined long-term\",\n        \"Applicability to human NASH was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovering that MATα1 localizes to liver mitochondria, interacts with MCJ, and facilitates SAMe-dependent lysine methylation that reduces MCJ levels introduced a novel post-translational mechanism controlling the abundance of the Complex I brake.\",\n      \"evidence\": \"Co-IP of MCJ with MATα1, mass spectrometry of lysine methylation, MAT1A overexpression and SAMe treatment in mice\",\n      \"pmids\": [\"38385082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How lysine methylation leads to reduced MCJ protein (degradation vs. altered stability) is not defined\",\n        \"Specific lysine residue(s) critical for regulation were not mutated to confirm functional relevance\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two studies expanded DNAJC15's physiological reach: loss of MCJ activates BAT thermogenesis via an eIF2α stress pathway even without UCP1, and DNAJC15 overexpression in ovarian cancer promotes lipid peroxidation-driven ferroptosis that sensitizes cells to cisplatin.\",\n      \"evidence\": \"MCJKO mice with in vivo CRISPR deletion of eIF2α for epistasis; DNAJC15 overexpression in ovarian cancer lines with ferroptosis rescue by Ferrostatin-1\",\n      \"pmids\": [\"39805849\", \"39809321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MCJ-dependent eIF2α activation is a direct signaling event or secondary to mitochondrial stress is unclear\",\n        \"Ferroptosis link derives from overexpression; relevance at endogenous MCJ levels in ovarian cancer is unconfirmed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Two mechanistic advances clarified MCJ's stress-responsive regulation and metabolic rewiring: OMA1 cleaves DNAJC15 during mitochondrial stress to restrict TIM23 import and OXPHOS biogenesis (triggering ER UPR via mislocalized preproteins), and elevated MCJ in cancer cells reroutes electron flux from Complex I to Complex II to support lipid-fueled respiration.\",\n      \"evidence\": \"In vitro OMA1 cleavage assays, AFG3L2 genetic manipulation, import assays, UPR reporters; Seahorse flux and Complex I/II activity assays with MCJ overexpression/knockdown in cancer cells\",\n      \"pmids\": [\"41760807\", \"41484063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of the OMA1-DNAJC15 cleavage complex and site specificity are not resolved\",\n        \"Whether Complex I-to-II electron rerouting requires DNAJC15's J-domain chaperone activity or a scaffolding role is unknown\",\n        \"Integration of OMA1-mediated degradation with MATα1-dependent methylation in controlling MCJ levels has not been examined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and mechanistic model explaining how DNAJC15 simultaneously regulates TIM23-dependent protein import and Complex I supercomplex stability — and how these two functions are coordinated under normal versus stress conditions — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of DNAJC15 in complex with either TIM23 or Complex I exists\",\n        \"Whether import and supercomplex functions are mediated by the same or distinct DNAJC15 pools is unknown\",\n        \"Relative contribution of OMA1 cleavage vs. MATα1-dependent methylation in setting MCJ steady-state levels in different tissues is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [0, 1, 3, 12]\n      },\n      {\n        \"term_id\": \"GO:0044183\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005739\",\n        \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 12]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1430728\",\n        \"supporting_discovery_ids\": [1, 3, 4, 7, 13]\n      },\n      {\n        \"term_id\": \"R-HSA-9609507\",\n        \"supporting_discovery_ids\": [0, 12]\n      },\n      {\n        \"term_id\": \"R-HSA-5357801\",\n        \"supporting_discovery_ids\": [2, 6, 10]\n      },\n      {\n        \"term_id\": \"R-HSA-8953897\",\n        \"supporting_discovery_ids\": [4, 11, 12]\n      }\n    ],\n    \"complexes\": [\n      \"TIM23 translocase\",\n      \"Complex I (NADH:ubiquinone oxidoreductase)\"\n    ],\n    \"partners\": [\n      \"MAGMAS\",\n      \"HSPA9\",\n      \"PPIF\",\n      \"OMA1\",\n      \"AFG3L2\",\n      \"MAT1A\",\n      \"ETV7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}