Pgam5,也称为Phosphoglycerate mutase family member 5,是一种线粒体磷酸酶。Pgam5在细胞内发挥多种生物学功能,包括调控线粒体动力学、线粒体自噬和细胞死亡。Pgam5通过去磷酸化Drp1蛋白,促进线粒体分裂,维持线粒体网络的动态平衡。此外,Pgam5还参与调控线粒体自噬,通过调控PINK1/Parkin信号通路,清除受损的线粒体,维持线粒体功能。Pgam5在细胞凋亡、坏死和坏死性凋亡等多种细胞死亡途径中发挥重要作用,影响细胞命运的决策。
在多种疾病中,Pgam5的表达和功能异常与疾病的发生和发展密切相关。例如,Pgam5的缺失导致视网膜色素上皮细胞(RPE)的加速衰老,增加细胞内活性氧(ROS)水平,增强mTOR和IRF/IFN-β信号通路,进而导致细胞衰老[1]。Pgam5还参与调控线粒体自噬,在CCCP诱导的线粒体损伤中,Pgam5通过DRP1调节PINK1/Parkin介导的自噬,发挥神经保护作用,抑制细胞凋亡[2]。此外,Pgam5的表达与肝损伤、心肌损伤、缺血性脑卒中和肾损伤等多种疾病的发生和发展相关。
在肝损伤中,Pgam5的缺失通过抑制DRP1的磷酸化,抑制线粒体分裂,减轻肝细胞损伤,促进肝组织修复[3]。在心肌损伤中,Pgam5的缺失通过调控线粒体动力学,减轻高血糖诱导的心肌功能障碍,保护心肌细胞[4]。在缺血性脑卒中中,Pgam5的表达上调导致细胞凋亡增加,线粒体功能障碍加重,加剧脑组织损伤[5]。在肾损伤中,Pgam5的缺失通过抑制坏死性凋亡通路,减轻肾小管上皮细胞损伤,促进肾组织修复[6]。
此外,Pgam5的表达和功能与肿瘤的发生和发展密切相关。例如,Pgam5的表达与皮肤黑色素瘤的预后不良相关,Pgam5的表达上调促进皮肤黑色素瘤的进展[7]。Pgam5的缺失导致肺炎症和病毒感染加剧,Pgam5参与调控ROS诱导的细胞死亡途径,称为“oxeiptosis”,发挥抗炎作用[8]。Pgam5的缺失导致T记忆干细胞(TSCM)减少,TSCM具有强大的抗肿瘤免疫能力,Pgam5的缺失抑制TSCM的形成,影响抗肿瘤免疫反应[9]。
综上所述,Pgam5是一种重要的线粒体磷酸酶,参与调控线粒体动力学、线粒体自噬和细胞死亡。Pgam5在多种疾病中发挥重要作用,包括肝损伤、心肌损伤、缺血性脑卒中和肾损伤等。Pgam5的表达和功能异常与肿瘤的发生和发展密切相关。因此,Pgam5可能成为治疗多种疾病和肿瘤的潜在靶点。
参考文献:
1. 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/
2. Park, Yun Sun, Choi, Su Eun, Koh, Hyun Chul. 2017. PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. In Toxicology letters, 284, 120-128. doi:10.1016/j.toxlet.2017.12.004. https://pubmed.ncbi.nlm.nih.gov/29241732/
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4. Peng, Jianzhong, Wang, Tao, Yue, Chao, Luo, Xianyan, Xiao, Peng. 2022. PGAM5: A necroptosis gene associated with poor tumor prognosis that promotes cutaneous melanoma progression. In Frontiers in oncology, 12, 1004511. doi:10.3389/fonc.2022.1004511. https://pubmed.ncbi.nlm.nih.gov/36523972/
5. Chen, Yingzhen, Huang, Jungang, Zhou, Hao, Lin, Jianguo, Tao, Jun. 2024. Pgam5 aggravates hyperglycemia-induced myocardial dysfunction through disrupting Phb2-dependent mitochondrial dynamics. In International journal of medical sciences, 21, 1194-1203. doi:10.7150/ijms.92872. https://pubmed.ncbi.nlm.nih.gov/38818468/
6. Holze, Cathleen, Michaudel, Chloé, Mackowiak, Claire, Ryffel, Bernhard, Pichlmair, Andreas. 2017. Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. In Nature immunology, 19, 130-140. doi:10.1038/s41590-017-0013-y. https://pubmed.ncbi.nlm.nih.gov/29255269/
7. Denk, Dominic, Petrocelli, Valentina, Conche, Claire, Rinsch, Chris, Greten, Florian R. 2022. Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy. In Immunity, 55, 2059-2073.e8. doi:10.1016/j.immuni.2022.09.014. https://pubmed.ncbi.nlm.nih.gov/36351375/
8. Ma, Chunli, Gao, Qing, Zhang, Li, Wu, Geng, Yang, Lei. . The Effect of PGAM5 on Regulating Mitochondrial Dysfunction in Ischemic Stroke. In Discovery medicine, 35, 1123-1133. doi:10.24976/Discov.Med.202335179.109. https://pubmed.ncbi.nlm.nih.gov/38058078/
9. Yu, Yihang, Chen, Meiling, Guo, Qitong, Zhang, Deying, Wei, Guanghui. 2023. Human umbilical cord mesenchymal stem cell exosome-derived miR-874-3p targeting RIPK1/PGAM5 attenuates kidney tubular epithelial cell damage. In Cellular & molecular biology letters, 28, 12. doi:10.1186/s11658-023-00425-0. https://pubmed.ncbi.nlm.nih.gov/36750776/