Cmpk2, or Cytidine/uridine monophosphate kinase 2, is a gene that regulates mtDNA replication. It is involved in various biological processes and pathways, such as the NLRP3 inflammasome activation pathway, and is associated with inflammation-related responses [1,2,3,5]. Genetic models, especially knockout (KO) mouse models, have been crucial in studying its functions.

In KO mouse models, Cmpk2-deficiency in microglia/macrophages suppresses neuroinflammation, reduces infarcts, and improves neurological outcomes after ischemic stroke, as it limits newly synthesized mtDNA and Ox-mtDNA formation, blocking NLRP3 inflammasome activation [1]. In spinal cord injury rats, knockdown of Cmpk2 inhibits NLRP3 activation and improves motor function [2]. In sepsis, a Cmpk2 inhibitor dracorhodin (DP) attenuates inflammation by regulating the NLRP3 inflammasome via the lipopolysaccharide-induced Cmpk2 pathway, and its effect is weakened in myeloid-specific Cmpk2-ablated mice [3]. In familial brain calcification, Cmpk2-KO mice recapitulate the mitochondrial dysfunction and brain calcification observed in patients [4]. In atherosclerosis, endothelial Gata6 deletion reduces monocyte recruitment and atherosclerotic lesion through the Cmpk2-Nlrp3 pathway [5]. In glucocorticoid-induced osteoporosis, inhibiting Cmpk2 expression alleviates cellular senescence and promotes osteogenic differentiation [6].

In conclusion, Cmpk2 is essential in regulating mitochondrial function, inflammation, and cell-related processes. The KO/conditional knockout (CKO) mouse models have significantly contributed to understanding its role in diseases like ischemic stroke, spinal cord injury, sepsis, familial brain calcification, atherosclerosis, and glucocorticoid-induced osteoporosis, providing potential therapeutic targets for these conditions.

References:

1. Guan, Xin, Zhu, Sitong, Song, Jinqian, Xu, Xiaojun, Pang, Tao. 2024. Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke. In Cell reports. Medicine, 5, 101522. doi:10.1016/j.xcrm.2024.101522. https://pubmed.ncbi.nlm.nih.gov/38701781/

2. Chen, Yi, Wu, Lei, Shi, Mengting, Shao, XiaoMei, Ma, Ruijie. 2022. Electroacupuncture Inhibits NLRP3 Activation by Regulating CMPK2 After Spinal Cord Injury. In Frontiers in immunology, 13, 788556. doi:10.3389/fimmu.2022.788556. https://pubmed.ncbi.nlm.nih.gov/35401582/

3. Zhang, Wendan, Jiang, Honghong, Huang, Pengli, Liu, Sanhong, Zhang, Weidong. . Dracorhodin targeting CMPK2 attenuates inflammation: A novel approach to sepsis therapy. In Clinical and translational medicine, 13, e1449. doi:10.1002/ctm2.1449. https://pubmed.ncbi.nlm.nih.gov/37859535/

4. Zhao, Miao, Su, Hui-Zhen, Zeng, Yi-Heng, Cheng, Xuewen, Chen, Wan-Jin. 2022. Loss of function of CMPK2 causes mitochondria deficiency and brain calcification. In Cell discovery, 8, 128. doi:10.1038/s41421-022-00475-2. https://pubmed.ncbi.nlm.nih.gov/36443312/

5. Wu, Wenrun, Bao, Wenzhen, Chen, Xiaoli, Zhang, Yuzhen, Zhuang, Tao. 2023. Endothelial Gata6 deletion reduces monocyte recruitment and proinflammatory macrophage formation and attenuates atherosclerosis through Cmpk2-Nlrp3 pathways. In Redox biology, 64, 102775. doi:10.1016/j.redox.2023.102775. https://pubmed.ncbi.nlm.nih.gov/37339559/

6. Cao, Nianping, Wang, Zhihang, Huang, Chongjun, Xu, Ying, Tian, Ye. 2023. Cmpk2 regulates mitochondrial function in glucocorticoid-induced osteoblast senescence and affects glucocorticoid-inhibited osteoblast differentiation. In Archives of gerontology and geriatrics, 114, 105080. doi:10.1016/j.archger.2023.105080. https://pubmed.ncbi.nlm.nih.gov/37269696/