PDF(Pubmed)
Abstract：
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.
摘要：
Ferroptosis,由脂质过氧化介导的非凋亡性细胞死亡的铁依赖性形式，与多种疾病的发病机理有关。亚细胞细胞器在铁凋亡的调节中起关键作用，但是线粒体贡献的潜在机制仍然不明确。视神经萎缩1（OPA1）是一种线粒体动力蛋白样GTP酶，控制线粒体形态发生，聚变,和能量学。这里,我们报道缺乏OPA1的人和小鼠细胞对铁凋亡有明显的抗性。与OPA1突变体的重组表明，铁凋亡致敏需要GTP酶活性，但与OPA1介导的线粒体融合无关。机械上,OPA1通过维持线粒体稳态和功能赋予铁凋亡的易感性，这有助于线粒体脂质活性氧（ROS）的产生和抑制ATF4介导的综合应激反应。一起,这些结果确定了OPA1控制的线粒体铁性凋亡调节轴，并为治疗性操纵疾病中这种形式的细胞死亡提供了机制见解。
