小柯机器人

德国科隆大学Thomas Langer团队近期取得重要工作进展，他们研究发现OMA1介导的综合应激反应可保护线粒体心肌病患者免受细胞铁死亡影响。相关研究成果2022年9月15日在线发表于《细胞—代谢》杂志上。

研究人员证明了细胞色素c氧化酶的组装因子Cox10的心脏特异性缺失导致小鼠线粒体心肌病，这与OXPHOS缺乏、溶酶体缺陷和线粒体形态异常有关。Cox10^-/-小鼠中线粒体肽酶Oma1的激活导致线粒体断裂和沿Oma1-Dele1-Atf4信号轴诱导综合应激反应（ISR）。Cox10^-/-小鼠中Oma1或Dele1的消融会加重心肌病。ISR抑制会损害心脏谷胱甘肽代谢，限制硒依赖的谷胱甘肽过氧化物酶Gpx4的积累，并增加心脏中的脂质过氧化，最终导致铁死亡。他们的结果证明了Oma1-Dele1介导的ISR在线粒体心肌病中的保护作用，并将铁死亡与OXPHOS缺乏和线粒体疾病联系起来。

据介绍，心肌病和心力衰竭是线粒体氧化磷酸化（OXPHOS）系统缺陷引起的线粒体疾病的常见表现。

附：英文原文

Title: OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy

Author: Sofia Ahola, Pablo Rivera Mejías, Steffen Hermans, Srikanth Chandragiri, Patrick Giavalisco, Hendrik Nolte, Thomas Langer

Issue&Volume: 2022-09-15

Abstract: Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies 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 mitochondrial 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 impairs 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 results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.

DOI: 10.1016/j.cmet.2022.08.017

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00360-6

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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