Ppif, also known as peptidylprolyl isomerase F and cyclophilin D, encodes a mitochondrial protein. It is a key component of the mitochondrial permeability transition pore (mPTP), which is involved in mitochondrial calcium efflux and regulation of mitochondrial function. Abnormal Ppif function can lead to mitochondrial dysfunction, influencing processes like apoptosis, necrosis, and cellular stress responses [1,2,3,4,5].

In a lung ischemia-reperfusion injury mouse model, PPIF inhibitors reduced neutrophil infiltration, NETs formation, and lung injury, suggesting neutrophil PPIF exacerbates this injury by promoting calcium overload-induced NETs formation [1]. In Nynrin-deficient mice, deletion of Nynrin activates Ppif, leading to mitochondrial dysfunction, while Ppif haploinsufficiency mitigates these effects, restoring hematopoietic stem cell function [2]. In septic mice, deletion of PPIF reduced lung and liver injuries, increasing survival [5].

In conclusion, Ppif plays a crucial role in mitochondrial function, especially in processes related to calcium handling and mPTP regulation. Gene-knockout mouse models have revealed its significance in diseases such as lung ischemia-reperfusion injury, hematopoietic stem cell-related disorders, and sepsis, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Wu, Wensi, Meng, Fanqing, Zhang, Huiying, Tian, Hui, Zhang, Xiaojun. 2024. Neutrophil PPIF exacerbates lung ischemia-reperfusion injury after lung transplantation by promoting calcium overload-induced neutrophil extracellular traps formation. In International immunopharmacology, 142, 113051. doi:10.1016/j.intimp.2024.113051. https://pubmed.ncbi.nlm.nih.gov/39236457/

2. Zhou, Chengfang, Kuang, Mei, Tao, Yin, Wang, Junping, Hou, Yu. 2024. Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening. In Cell stem cell, 31, 1359-1375.e8. doi:10.1016/j.stem.2024.06.007. https://pubmed.ncbi.nlm.nih.gov/38955185/

3. Protasoni, Margherita, López-Polo, Vanessa, Stephan-Otto Attolini, Camille, Kovatcheva, Marta, Serrano, Manuel. 2024. Cyclophilin D plays a critical role in the survival of senescent cells. In The EMBO journal, 43, 5972-6000. doi:10.1038/s44318-024-00259-2. https://pubmed.ncbi.nlm.nih.gov/39448884/

4. Biczo, Gyorgy, Vegh, Eszter T, Shalbueva, Natalia, Gukovsky, Ilya, Gukovskaya, Anna S. 2017. Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models. In Gastroenterology, 154, 689-703. doi:10.1053/j.gastro.2017.10.012. https://pubmed.ncbi.nlm.nih.gov/29074451/

5. Ni, Rui, Ji, Xiao-Yun, Cao, Ting, Su, Zhao-Liang, Peng, Tian-Qing. 2024. Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction. In Acta pharmacologica Sinica, 46, 976-988. doi:10.1038/s41401-024-01424-3. https://pubmed.ncbi.nlm.nih.gov/39623043/