DNAJC19, a member of the DNAJ heat shock protein (Hsp40) family, is located within the inner mitochondrial membrane. It plays a crucial role in regulating the function and localization of mitochondrial Hsp70 (MtHsp70) and is involved in mitochondrial protein import machinery [3,5]. It also forms a complex with prohibitins to regulate cardiolipin remodeling, which is essential for mitochondrial morphogenesis [4].

Mutations in DNAJC19 cause Dilated Cardiomyopathy with Ataxia Syndrome (DCMA). In human iPSC-derived cardiomyocytes with mutant DNAJC19 lacking the conserved DnaJ interaction domain, there are mitochondrial fragmentation, abnormal cristae formation, increased mitochondrial respiration, and altered substrate utilization [2]. In NSCLC, DNAJC19 expression is higher in tumors than adjacent non-cancerous tissues. shRNA-mediated knockdown of DNAJC19 in A549 lung cancer cells inhibits cell growth, viability, migration, and invasion, and represses tumor xenograft growth and lung metastasis by regulating the PI3K/AKT signaling pathway [1].

In conclusion, DNAJC19 is essential for mitochondrial function, including mitochondrial morphogenesis and cardiolipin remodeling. Its dysregulation is associated with DCMA and NSCLC. Studies using gene-edited cell lines and knockdown models in cancer cells have revealed its role in these disease conditions, providing potential therapeutic targets.

References:

1. Zhou, Ji, Peng, Yang, Gao, Ying-Chun, Liu, Tao, Ren, Tao. 2021. Targeting DNAJC19 overcomes tumor growth and lung metastasis in NSCLC by regulating PI3K/AKT signaling. In Cancer cell international, 21, 338. doi:10.1186/s12935-021-02054-z. https://pubmed.ncbi.nlm.nih.gov/34217321/

2. Janz, Anna, Walz, Katharina, Cirnu, Alexandra, Duff, Henry J, Gerull, Brenda. 2023. Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes. In Molecular metabolism, 79, 101859. doi:10.1016/j.molmet.2023.101859. https://pubmed.ncbi.nlm.nih.gov/38142971/

3. Al Tuwaijri, Abeer, Alyafee, Yusra, Alharbi, Mashael, Umair, Muhammad, Alfadhel, Majid. 2022. Novel homozygous pathogenic mitochondrial DNAJC19 variant in a patient with dilated cardiomyopathy and global developmental delay. In Molecular genetics & genomic medicine, 10, e1969. doi:10.1002/mgg3.1969. https://pubmed.ncbi.nlm.nih.gov/35611801/

4. Richter-Dennerlein, Ricarda, Korwitz, Anne, Haag, Mathias, Rugarli, Elena I, Langer, Thomas. 2014. DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling. In Cell metabolism, 20, 158-71. doi:10.1016/j.cmet.2014.04.016. https://pubmed.ncbi.nlm.nih.gov/24856930/

5. Chen, Guangduo, Bai, Rui, Huang, Pufeng, Ni, Jie, Chen, Lianglong. 2024. Generation of a homozygous DNAJC19 knockout human embryonic stem cell line by Nuclease technology system. In Stem cell research, 77, 103427. doi:10.1016/j.scr.2024.103427. https://pubmed.ncbi.nlm.nih.gov/38696852/