The mitochondrial permeability transition pore (PTP) is a Ca²⁺-activated channel that plays a key role in cell death. Thiol oxidation facilitates PTP opening, yet the targets and molecular mechanisms still await a definition. Here, we investigate the role of C141 of F-ATP synthase oligomycin sensitivity conferral protein (OSCP) subunit in PTP modulation by oxidation. We find that the OSCP C141S mutation confers resistance to PTP opening and cell death by diamide and MitoParaquat only when cyclophilin D (CyPD) has been ablated, a protective role that can be explained by CyPD shielding C141 from oxidants. The mutation decreases apoptosis in zebrafish embryos, indicating that this OSCP residue is involved in development. Site-directed mutagenesis in yeast suggests that other conserved cysteines in the α, γ, and c subunits of F-ATP synthase are not involved in PTP modulation. Thus, OSCP provides a strategic site that regulates PTP opening by the interplay between CyPD (un)binding and thiol oxidation-reduction.

线粒体通透性过渡孔（PTP）是Ca ²⁺激活的通道在细胞死亡中起关键作用。硫醇氧化促进了PTP的开放，但是靶标和分子机制仍在等待定义。在这里，我们调查的F-ATP合酶寡霉素敏感性赋予蛋白（OSCP）亚基的C141在PTP调节氧化中的作用。我们发现，仅当亲环蛋白D（CyPD）被消除时，OSCP C141S突变才赋予二酰胺和MitoParaquat对PTP开放和细胞死亡的抵抗力，这种保护作用可以由CyPD屏蔽C141免受氧化剂影响。该突变减少了斑马鱼胚胎中的细胞凋亡，表明该OSCP残基参与了发育。酵母中的定点诱变表明F-ATP合酶的α，γ和c亚基中的其他保守半胱氨酸不参与PTP调节。从而，