Mitochondrial permeability transition mediated by MTCH2 and F‐ATP synthase contributes to ferroptosis defense

The opening of the mitochondrial permeability transition pore (PTP), a Ca 2+ ‐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.