Pgam5, also known as phosphoglycerate mutase family member 5, is a mitochondrial serine/threonine protein phosphatase. It plays a crucial role in mitochondrial dynamics, including mitochondrial fission, fusion, biogenesis, and mitophagy. These processes are essential for maintaining mitochondrial homeostasis, and imbalances can lead to various programmed cell death processes and cellular senescence. Pgam5 functions mainly through protein-protein interactions and its specific phosphatase activity, and is regulated by mitochondrial proteases [1,2].

Deletion of Pgam5 in mice has provided valuable insights. In retinal pigment epithelial (RPE) cells, Pgam5 deletion leads to accelerated senescence both in vitro and in vivo. Mechanistically, Pgam5 is required for mitochondrial fission by dephosphorylating DRP1; its deletion increases mitochondrial fusion and decreases turnover, elevating cellular ATP and ROS levels, enhancing mTOR and IRF/IFN-β signaling, and thus promoting cellular senescence [2]. In macrophages, conditional knockout of Pgam5 greatly alleviates osteoarthritis symptoms, as Pgam5 enhances M1 polarization and inhibits M2 polarization in macrophages, and its knockout promotes anabolic metabolism of chondrocytes [3]. Genetic deletion of Pgam5 also ameliorates skeletal muscle atrophy in tumor-bearing mice by repressing excessive myoblast mitophagy [4].

In conclusion, Pgam5 is essential for regulating mitochondrial dynamics and related cellular processes. Studies using Pgam5 knockout or conditional knockout mouse models have revealed its roles in age-related diseases such as cellular senescence, osteoarthritis, and cancer-associated muscle wasting, providing important insights into the mechanisms of these diseases and potential therapeutic targets.

References:

1. Cheng, Meiyu, Lin, Nan, Dong, Delu, Su, Jing, Sun, Liankun. 2020. PGAM5: A crucial role in mitochondrial dynamics and programmed cell death. In European journal of cell biology, 100, 151144. doi:10.1016/j.ejcb.2020.151144. https://pubmed.ncbi.nlm.nih.gov/33370650/

2. Yu, Bo, Ma, Jing, Li, Jing, Wang, Zhigao, Wang, Shusheng. 2020. Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics. In Nature communications, 11, 2549. doi:10.1038/s41467-020-16312-7. https://pubmed.ncbi.nlm.nih.gov/32439975/

3. Liu, Yuhang, Hao, Ruihan, Lv, Jia, Lu, Wei, Zhang, Xiaoling. 2024. Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis. In Bone research, 12, 15. doi:10.1038/s41413-024-00318-8. https://pubmed.ncbi.nlm.nih.gov/38433252/

4. Zhang, Qingyuan, Chen, Chunhui, Ma, Ye, La, Lei, Sun, Xuegang. 2024. PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting. In Autophagy, 20, 2205-2220. doi:10.1080/15548627.2024.2360340. https://pubmed.ncbi.nlm.nih.gov/38919131/