DnaJC15, also known as Methylation-controlled J protein (MCJ), is a mitochondrial protein. It localizes at the mitochondrial inner membrane and interacts preferentially with complex I of the electron transfer chain, functioning as a negative regulator of the respiratory chain [5]. It is involved in pathways related to mitochondrial metabolism, oxidative stress response, and lipid metabolism, and is important for maintaining normal mitochondrial function and cellular metabolism [4]. Genetic models, such as knockout mouse models, are valuable for studying its function.

In MCJKO mice, even without UCP1, there is elevated brown adipose tissue (BAT) thermogenesis, with changes in mitochondrial morphology and involvement of the eIF2α mediated stress response, indicating that MCJ/DnaJC15 is a regulator of BAT thermogenesis [1]. Silencing hepatic MCJ in mouse models of non-alcoholic fatty liver disease (NAFLD) reduces liver lipid accumulation and fibrosis by enhancing mitochondrial fatty acid oxidation, as MCJ is an endogenous negative regulator of respiratory chain Complex I [2]. In breast cancer cells, ETV7-mediated repression of DnaJC15 leads to doxorubicin resistance, and in ovarian cancer cells, high levels of DnaJC15 are associated with increased sensitivity to cisplatin and induction of ferroptosis [3,4].

In conclusion, DnaJC15 plays crucial roles in mitochondrial-related biological processes. Studies using KO/CKO mouse models have revealed its significance in obesity, NAFLD, breast cancer, and ovarian cancer. Understanding DnaJC15's functions provides insights into the mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Cicuéndez, Beatriz, Mora, Alfonso, López, Juan Antonio, Folgueira, Cintia, Sabio, Guadalupe. 2025. Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis. In Nature communications, 16, 229. doi:10.1038/s41467-024-54353-4. https://pubmed.ncbi.nlm.nih.gov/39805849/

2. Barbier-Torres, Lucía, Fortner, Karen A, Iruzubieta, Paula, Martínez-Chantar, María Luz, Rincón, Mercedes. 2020. Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation. In Nature communications, 11, 3360. doi:10.1038/s41467-020-16991-2. https://pubmed.ncbi.nlm.nih.gov/32620763/

3. Alessandrini, Federica, Pezzè, Laura, Menendez, Daniel, Resnick, Michael A, Ciribilli, Yari. 2018. ETV7-Mediated DNAJC15 Repression Leads to Doxorubicin Resistance in Breast Cancer Cells. In Neoplasia (New York, N.Y.), 20, 857-870. doi:10.1016/j.neo.2018.06.008. https://pubmed.ncbi.nlm.nih.gov/30025229/

4. Miglietta, Stefano, Sollazzo, Manuela, Gherardi, Iacopo, Ghelli, Anna Maria, Porcelli, Anna Maria. 2025. Mitochondrial chaperonin DNAJC15 promotes vulnerability to ferroptosis of chemoresistant ovarian cancer cells. In Open biology, 15, 240151. doi:10.1098/rsob.240151. https://pubmed.ncbi.nlm.nih.gov/39809321/

5. Hatle, Ketki M, Gummadidala, Phani, Navasa, Nicolás, Anguita, Juan, Rincon, Mercedes. 2013. MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations. In Molecular and cellular biology, 33, 2302-14. doi:10.1128/MCB.00189-13. https://pubmed.ncbi.nlm.nih.gov/23530063/