OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response

Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.铁死亡（Ferroptosis）是一种铁依赖的非凋亡性细胞死亡形式，由脂质过氧化介导，现已被发现与多种疾病的发病机制密切相关。亚细胞器在铁死亡的调控过程中发挥关键作用，但线粒体的贡献机制仍未得到清晰阐明。视神经萎缩蛋白1（Optic atrophy 1, OPA1）是一种调控线粒体形态发生、融合及能量代谢的线粒体动力蛋白样GTP酶。本研究发现，缺失OPA1的人源与鼠源细胞对铁死亡具有显著抗性。通过OPA1突变体进行基因回补实验证实，铁死亡致敏效应依赖于OPA1的GTP酶活性，但与OPA1介导的线粒体融合过程无关。从机制层面来看，OPA1通过维持线粒体稳态与功能，同时促进线粒体脂质活性氧（reactive oxygen species, ROS）的生成，并抑制激活转录因子4（ATF4）介导的整合应激反应，从而使细胞对铁死亡易感。综上，本研究结果明确了一条由OPA1调控的线粒体铁死亡信号轴，为在疾病中治疗性干预该类细胞死亡方式提供了机制层面的理论依据。