Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Shanghai, China; Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
J Biol Chem. 2022 May;298(5):101858. doi: 10.1016/j.jbc.2022.101858. Epub 2022 Mar 23.
The mitochondrial permeability transition pore (PTP) is a Ca-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.
线粒体通透性转换孔（PTP）是一种 Ca2+依赖性的巨型通道，在线粒体生理学和细胞命运中发挥着重要作用。亲环素 D（CyPD）是一种特征明确的 PTP 调节剂，其与 PTP 的结合有利于孔的开放。先前的研究表明，p53 与 CyPD 发生物理相互作用，并在坏死过程中打开 PTP。越来越多的研究还表明，F-ATP 合酶有助于 PTP 的调节和形成。F-ATP 合酶 IF1（线粒体 ATP 合酶抑制因子 1）是 F-ATP 合酶活性的天然抑制剂；然而，IF1 是否参与 PTP 开放的调节基本上是未知的。在这里，我们通过钙保留能力测定表明 IF1 的过表达通过打开 PTP 促进线粒体通透性转换。有趣的是，我们表明 IF1 可以与 p53-CyPD 复合物相互作用并促进细胞死亡。我们还表明，IF1 的存在对于 p53-CyPD 复合物的形成是必要的。因此，我们认为 IF1 通过与 p53-CyPD 复合物相互作用来调节 PTP，并且 IF1 对于 p53-CyPD 复合物对 PTP 开放的诱导作用是必要的。
