| 2013 |
MCJ/DnaJC15 localizes to the mitochondrial inner membrane and interacts preferentially with Complex I of the electron transport chain, where it 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. |
Subcellular fractionation, Co-immunoprecipitation, functional respiratory chain assays in MCJ-deficient cells/mice |
Molecular and cellular biology |
High |
23530063
|
| 2012 |
MCJ is anchored in the mitochondrial inner membrane with its C-terminal J domain facing the matrix. It forms a stable subcomplex with MAGMAS, a component of the mitochondrial import motor, and both interact with core components of the TIM23 pre-protein translocase. The recombinant soluble MCJ domain stimulates the ATPase activity of mtHsp70 (mortalin), the central component of the TIM23 import motor, and this stimulation is counteracted by MAGMAS. Loss of MCJ impairs pre-protein import into mitochondria, and MCJ can functionally substitute for Tim14, the essential J co-chaperone of the yeast import motor. |
Submitochondrial fractionation, Co-immunoprecipitation, in vitro ATPase assay with recombinant proteins, yeast complementation assay, import assay in MCJ-depleted mitochondria |
Human molecular genetics |
High |
23263864
|
| 2014 |
DnaJC15 overexpression promotes mitochondrial permeability transition pore (MPTP) opening and apoptosis upon cisplatin treatment, while reduced DnaJC15 suppresses MPTP activation. DnaJC15 exerts its pro-apoptotic function through cyclophilin D (CypD), recruiting and coupling CypD with the mitochondrial permeability transition machinery. |
Overexpression and knockdown of DnaJC15 in cells, MPTP opening assays, Co-immunoprecipitation with CypD, cisplatin treatment with apoptosis readouts |
Cell death & disease |
Medium |
24603329
|
| 2016 |
MCJ acts as an endogenous brake for mitochondrial respiration in CD8+ T cells by interfering with formation of electron transport chain respiratory supercomplexes. MCJ deficiency enhances oxidative phosphorylation and subcellular ATP accumulation, which selectively increases secretion (but not expression) of IFN-γ. MCJ also modulates effector CD8+ T cell metabolism during the contraction phase, resulting in superior memory T cell formation. |
Metabolic profiling (Seahorse), supercomplex analysis, MCJ-deficient mice, cytokine secretion assays, influenza infection model |
Immunity |
High |
27234056
|
| 2004 |
Cell type-specific expression of MCJ is controlled by methylation of a CpG island within its first exon (not the promoter). The CpG island is methylated and MCJ is not expressed in epithelial cells, but unmethylated and expressed in lymphocyte or fibroblast cells. CpG island methylation is associated with loss of histone acetylation at both the island and the promoter region, indicating methylation-directed chromatin remodeling leads to gene inactivation. |
Bisulfite sequencing, RT-PCR, chromatin immunoprecipitation (ChIP) for histone acetylation marks |
Carcinogenesis |
High |
14729589
|
| 2017 |
APAP (acetaminophen) treatment interferes with formation of mitochondrial respiratory supercomplexes via MCJ, leading to decreased ATP production and increased ROS generation. In vivo inhibition of MCJ expression protects the liver from APAP-induced injury. |
Supercomplex native gel analysis, ROS and ATP measurement, siRNA-mediated MCJ inhibition in mouse APAP liver injury model |
Nature communications |
High |
29233977
|
| 2020 |
MCJ is an endogenous negative regulator of respiratory chain Complex I in hepatocytes. Decreasing MCJ expression (via nanoparticle- or GalNAc-formulated siRNA) enhances hepatocyte capacity for β-oxidation of fatty acids, reduces lipid accumulation, and decreases hepatocyte damage and fibrosis in multiple NASH mouse models. |
siRNA-mediated MCJ silencing in vivo (nanoparticle/GalNAc formulations), β-oxidation assay, lipid quantification, histological fibrosis scoring in NASH mouse models |
Nature communications |
High |
32620763
|
| 2018 |
ETV7, a transcriptional repressor of the ETS family induced by doxorubicin, directly binds the DNAJC15 promoter and represses DNAJC15 expression, leading to doxorubicin resistance in breast cancer cells. ETV7-mediated resistance involves increased doxorubicin efflux via nuclear pumps, which is partially rescued by DNAJC15 upregulation. |
ChIP/promoter binding assay for ETV7 at DNAJC15 promoter, ETV7 overexpression with DNAJC15 expression measurement, drug efflux assays, DNAJC15 rescue experiments |
Neoplasia |
Medium |
30025229
|
| 2019 |
Induction of glycolysis in CD8+ T cells upregulates MCJ expression, and MCJ acts synergistically with glycolysis to promote caspase-3 activity. MCJ-deficient effector CD8+ T cells show reduced glycolysis and considerably less active caspase-3 compared to wild-type cells. In non-glycolytic IL-15-cultured CD8+ T cells, MCJ expression is repressed by methylation, paralleling reduced caspase-3 activity and increased survival. |
MCJ-deficient mouse CD8+ T cells, caspase-3 activity assays, glycolysis measurements, methylation analysis of MCJ locus in IL-2 vs IL-15 cultured T cells |
Frontiers in cell and developmental biology |
Medium |
30915331
|
| 2024 |
S-adenosylmethionine (SAMe) negatively regulates MCJ expression in the liver. MCJ is methylated at lysine residues and interacts with MATα1 (methionine adenosyltransferase alpha 1) within liver mitochondria, likely to facilitate its methylation. Deficiency in MATα1 leads to MCJ upregulation, while MAT1A overexpression and SAMe treatment reduce MCJ expression. |
Co-immunoprecipitation of MCJ with MATα1 in liver mitochondria, mass spectrometry identification of lysine methylation on MCJ, MAT1A overexpression, SAMe treatment, MATα1-KO model |
International journal of biological sciences |
Medium |
38385082
|
| 2025 |
DNAJC15 overexpression in ovarian cancer cells induces lipid peroxidation and ferroptosis, increasing sensitivity to cisplatin. Inhibition of lipid peroxidation with Ferrostatin-1 reduces ferroptosis vulnerability and recovers cisplatin resistance, establishing a mechanistic link between DNAJC15, ferroptosis induction, and chemosensitivity. |
DNAJC15 overexpression, lipid peroxidation assays, Ferrostatin-1 rescue experiments, cisplatin sensitivity assays in ovarian cancer cells |
Open biology |
Medium |
39809321
|
| 2026 |
The mitochondrial protease OMA1 cleaves DNAJC15, promoting its degradation by the m-AAA protease AFG3L2 under cellular stress conditions. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. |
OMA1 cleavage assay, AFG3L2 protease assay, mitochondrial protein import assay in DNAJC15-deficient cells, ER stress/UPR reporter assays |
Nature structural & molecular biology |
High |
41760807
|
| 2025 |
Absence of MCJ in brown adipose tissue (BAT) promotes thermogenesis even in the absence of UCP1. MCJKO mice show altered mitochondrial morphology consistent with BAT activation, and the eIF2α-mediated stress response is required for this enhanced thermogenesis, as in vivo CRISPR deletion of eIF2α in MCJKO mice abrogates the thermogenic phenotype. |
MCJKO mouse model, electron microscopy of mitochondrial morphology, proteomics, in vivo CRISPR deletion of eIF2α in MCJKO mice, thermogenesis measurement |
Nature communications |
High |
39805849
|
| 2026 |
Elevated MCJ levels in cancer cells promote aggressive proliferative and migratory phenotypes by mediating a preferential rerouting of electron flux through Complex II (succinate dehydrogenase complex) rather than Complex I. This results in suppressed glycolysis, increased lipid accumulation and oxidation, maintained NADH levels, and preserved respiratory output despite Complex I uncoupling. |
MCJ overexpression in cancer cells, Seahorse metabolic flux analysis, Complex I/II activity assays, lipid accumulation and oxidation measurements, proliferation and migration assays |
Cell death & disease |
Medium |
41484063
|