DNAJC15

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).

1. 2004 Medium

   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

   PMID:14729589

   Open questions at the time

   • Writers and erasers of this CpG methylation mark were not identified
   • Whether methylation-dependent silencing is causal for cancer chemoresistance was not tested
2. 2012 High

   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

   PMID:23263864

   Open questions at the time

   • 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
3. 2013 High

   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

   PMID:23530063

   Open questions at the time

   • 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
4. 2014 Medium

   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

   PMID:24603329

   Open questions at the time

   • 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
5. 2016 High

   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

   PMID:27234056

   Open questions at the time

   • 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
6. 2017 High

   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

   PMID:29233977

   Open questions at the time

   • Mechanism by which APAP upregulates MCJ protein levels was not determined
   • Long-term effects of MCJ silencing on liver homeostasis were not assessed
7. 2018 Medium

   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

   PMID:30025229

   Open questions at the time

   • 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
8. 2019 Medium

   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

   PMID:30915331

   Open questions at the time

   • 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
9. 2020 High

   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

   PMID:32620763

   Open questions at the time

   • Whether chronic MCJ silencing causes compensatory metabolic reprogramming or ROS toxicity was not examined long-term
   • Applicability to human NASH was not demonstrated
10. 2024 Medium

    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

    PMID:38385082

    Open questions at the time

    • 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
11. 2025 High

    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

    PMID:39805849 PMID:39809321

    Open questions at the time

    • 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
12. 2026 High

    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

    PMID:41484063 PMID:41760807

    Open questions at the time

    • 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

• 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.
• 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