CKMT1, the ubiquitous mitochondrial creatine kinase, is crucial for energy metabolism, controlling the regeneration of ADP and phosphocreatine in the creatine cycle [2]. It is involved in maintaining mitochondrial homeostasis, and its function is associated with multiple biological processes such as cell viability, apoptosis, and cell migration [3,4]. Gene knockout models have been valuable in elucidating its role.

In IBD, neutrophil-derived PAD4 citrullinates CKMT1 at the R242 site in intestinal epithelial cells (IECs), reducing its protein stability via autophagy, impairing mitochondrial homeostasis, and exacerbating mucosal inflammation. IEC-specific depletion of CKMT1 further worsens intestinal inflammation and apoptosis in colitis mice [1]. In white/beige adipose tissue, CKMT1 is dispensable for mitochondrial bioenergetics and energy expenditure, as shRNA-mediated reduction in cultured adipocytes and CKMT1 ablation in mice did not affect these processes [2]. In breast cancer, while CKMT1 is highly expressed in primary tumors promoting cell viability, its downregulation in metastasis drives up mitochondrial ROS levels, contributing to cell migration and invasion [3]. In colitis, CKMT1 deficiency in IECs leads to increased TNF-α-induced mitochondrial ROS generation via reverse electron transfer, promoting mPTP opening and cell apoptosis [4].

In summary, CKMT1 plays a vital role in maintaining mitochondrial function and intestinal homeostasis. Its deficiency is associated with exacerbation of diseases like IBD and colitis. The use of CKMT1 knockout or conditional knockout mouse models has been instrumental in uncovering its role in these disease conditions, providing potential therapeutic targets for these diseases.

References:

1. Wang, Shuling, Song, Yihang, Wang, Zhijie, Ren, Xingxing, Bai, Yu. 2024. Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease. In Cellular & molecular immunology, 21, 620-633. doi:10.1038/s41423-024-01158-6. https://pubmed.ncbi.nlm.nih.gov/38720063/

2. Politis-Barber, Valerie, Petrick, Heather L, Raajendiran, Arthe, Watt, Matthew J, Holloway, Graham P. 2022. Ckmt1 is Dispensable for Mitochondrial Bioenergetics Within White/Beige Adipose Tissue. In Function (Oxford, England), 3, zqac037. doi:10.1093/function/zqac037. https://pubmed.ncbi.nlm.nih.gov/37954502/

3. Ayyappan, Vinay, Jenkinson, Nicole M, Tressler, Caitlin M, Argani, Pedram, Glunde, Kristine. 2024. Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression. In Cell reports, 43, 114121. doi:10.1016/j.celrep.2024.114121. https://pubmed.ncbi.nlm.nih.gov/38615320/

4. Wang, Zhijie, Wu, Haicong, Chang, Xin, Wang, Shuling, Bai, Yu. 2025. CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis. In Cell death & disease, 16, 177. doi:10.1038/s41419-025-07504-4. https://pubmed.ncbi.nlm.nih.gov/40089459/