Mitochondrial ATP synthase inhibitory factor 1 interacts with the p53–cyclophilin D complex and promotes opening of the permeability transition pore

• Published in: The Journal of biological chemistry Vol. 298; no. 5; p. 101858
• Main Author: Guo, Lishu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2022; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Triphosphate; ATPase Inhibitory Protein; cyclophilin D; F-ATP synthase inhibitory factor 1; mitochondria; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; mitochondrial permeability transition; Mitochondrial Permeability Transition Pore; p53; Peptidyl-Prolyl Isomerase F - genetics; Peptidyl-Prolyl Isomerase F - metabolism; Proteins - genetics; Proteins - metabolism; Proton-Translocating ATPases - genetics; Proton-Translocating ATPases - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; HEK293T; cyclophilin D; tBHP; mitochondria; ANT; IP; mitochondrial permeability transition; OXPHOS; CyPD; F-ATP synthase inhibitory factor 1; PTP; p53; CsA; DMEM; PDAC; OSCP; CRC; IF1; KCl; PEI; sgRNA; ROS; PPIF; HA
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2022.101858

The mitochondrial permeability transition pore (PTP) is a Ca2+-dependent megachannel that plays an important role in mitochondrial physiology and cell fate. Cyclophilin D (CyPD) is a well-characterized PTP regulator, and its binding to the PTP favors pore opening. It has previously been shown that p53 physically interacts with CyPD and opens the PTP during necrosis. Accumulating studies also suggest that the F-ATP synthase contributes to the regulation and formation of the PTP. F-ATP synthase IF1 (mitochondrial ATP synthase inhibitory factor 1) is a natural inhibitor of F-ATP synthase activity; however, whether IF1 participates in the modulation of PTP opening is basically unknown. Here, we demonstrate using calcium retention capacity assay that IF1 overexpression promotes mitochondrial permeability transition via opening of the PTP. Intriguingly, we show that IF1 can interact with the p53–CyPD complex and facilitate cell death. We also demonstrate that the presence of IF1 is necessary for the formation of p53–CyPD complex. Therefore, we suggest that IF1 regulates the PTP via interaction with the p53–CyPD complex, and that IF1 is necessary for the inducing effect of p53–CyPD complex on PTP opening.