Guo Lishu
Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
FEBS Lett. 2025 Feb;599(3):352-366. doi: 10.1002/1873-3468.15008. Epub 2024 Sep 3.
The opening of the mitochondrial permeability transition pore (PTP), a Ca-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.
线粒体通透性转换孔（PTP）是位于线粒体内膜的一种钙依赖性孔道，其开放会引发线粒体外膜通透性增加（MOMP）并导致细胞器破裂。然而，PTP诱导MOMP的潜在机制仍不清楚。线粒体载体同源物2（MTCH2）通过促进tBID募集到线粒体来介导MOMP过程。在此，我们表明MTCH2与亲环蛋白D（CyPD）结合，并通过与亚基j相互作用促进F-ATP合酶的二聚化。MTCH2与亚基j之间的相互作用协调MOMP和PTP，以介导线粒体通透性转换的发生。敲低CyPD、MTCH2和亚基j会使细胞对RSL3诱导的铁死亡显著敏感，而MitoTEMPO可预防这种情况，这表明线粒体通透性转换介导铁死亡防御。
