OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy
OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy
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DOI：
10.1016/j.cmet.2022.08.017
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发表时间：
2022-11-01
期刊：
影响因子：
29
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
--
作者：
Ahola, Sofia;Mejias, Pablo Rivera;Langer, Thomas
心肌病和心力衰竭是由线粒体氧化磷酸化（OXPHOS）系统缺陷引起的线粒体疾病的常见表现。在这里，我们证明了心脏特异性损失的组装因子Cox 10的细胞色素c氧化酶导致小鼠的线粒体心肌病，这是与OXPHOS缺乏症，溶酶体缺陷，和异常的线粒体形态。在Cox 10-“小鼠中，线粒体肽酶Oma 1的激活导致线粒体断裂并诱导沿Oma 1-Dele 1-Atf 4信号传导轴的整合应激反应（ISR）沿着。在Cox 10-“小鼠中消融Oma 1或Dele 1可导致心肌病。ISR抑制损害心脏谷胱甘肽代谢，限制谷胱甘肽过氧化物酶Gpx 4的硒依赖性积累，并增加心脏中的脂质过氧化，最终导致铁凋亡。我们的结果证明了Oma 1-Del 1介导的ISR在线粒体心肌病中的保护作用，并将铁细胞下垂与OXPHOS缺陷和线粒体疾病联系起来。
Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by defi-ciencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10-'- mice results in mito-chondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10-'- mice aggravates cardiomyopathy. ISR inhibition im-pairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our re-sults demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.