Mouse heart proteomics in Oma1 and Cox10 deficient mice

Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation system of mitochondria (OXPHOS). 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 and ultrastructure. We demonstrate activation of the mitochondrial peptidase Oma1 in Cox10-/- mice, which results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signalling axis. Ablation of Oma1 or Dele1 in Cox10-/- mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, decreases the levels 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-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.

心肌病与心力衰竭是线粒体氧化磷酸化系统（OXPHOS）缺陷所致线粒体疾病的常见临床表现。本研究证实，小鼠心脏特异性敲除细胞色素c氧化酶组装因子Cox10可诱发线粒体心肌病，该表型伴随OXPHOS缺陷、溶酶体功能异常以及线粒体形态与超微结构紊乱。研究发现，Cox10敲除（Cox10-/-）小鼠的线粒体肽酶Oma1被激活，进而引发线粒体碎片化，并通过Oma1-Dele1-Atf4信号轴激活整合应激反应（ISR）。在Cox10-/-小鼠中敲除Oma1或Dele1会加重线粒体心肌病。抑制整合应激反应将损害心脏谷胱甘肽代谢，降低谷胱甘肽过氧化物酶Gpx4的表达水平，并加剧心脏脂质过氧化，最终诱发铁死亡。本研究结果表明，Oma1介导的整合应激反应在线粒体心肌病中发挥保护作用，并将铁死亡与OXPHOS缺陷及线粒体疾病建立了功能关联。