Integrated stress response couples mitochondria protein translation with oxidative stress control

Under stress conditions, cells elicit integrated stress response (ISR) to cope with intracellular and extracellular disturbances. However, its role in ischemic heart disease remains to be elucidated. Here, we show that oxygen deprivation in cardiomyocytes triggers significant changes in protein translation. Importantly, ischemia and ischemia/reoxygenation leads to suppression of protein synthesis, which is caused by activation of the PERK/eIF2α axis of ISR. At the functional level, cardiac specific elimination of PERK exacerbates cardiac response to ischemia/reperfusion whereas selective activation of PERK in the heart confers cardioprotection against reperfusion injury. Mechanistically, PERK-mediated improvement in cardiomyocyte survival depends on suppression of protein synthesis and consequently relieves energetic demand on mitochondria. We went further to show that mitochondrial complex components are targeted by protein translation suppression, which significantly diminishes mitochondria-associated production of reactive oxygen species. Indeed, pharmacological activation of ISR protects the heart from ischemia/reperfusion damage, even after the release of occluded coronary artery, highlighting clinical significance for myocardial infarction. Taken together, these findings suggest that ISR improves cell survival through selectively suppressing mitochondrial protein synthesis and reducing oxidative stress in ischemic heart disease.在应激条件下，细胞会激活整合应激反应（integrated stress response, ISR）以应对细胞内与细胞外的各类干扰因素。然而，该反应在缺血性心脏病（ischemic heart disease）中的作用仍有待阐明。本研究发现，心肌细胞（cardiomyocytes）的氧剥夺会引发蛋白质翻译（protein translation）过程的显著改变。值得注意的是，缺血以及缺血/再灌注（ischemia/reperfusion）会抑制蛋白质合成（protein synthesis），这一过程由整合应激反应的PERK/eIF2α通路（PERK/eIF2α axis）激活所介导。在功能层面，心肌特异性敲除PERK会加重心肌对缺血/再灌注的损伤反应，而心脏中PERK的选择性激活则可赋予心肌对抗再灌注损伤的保护作用。从机制上看，PERK介导的心肌细胞存活改善依赖于蛋白质合成的抑制，进而减轻线粒体的能量负荷。本研究进一步证实，蛋白质翻译抑制会靶向作用于线粒体复合物组分（mitochondrial complex components），从而显著减少线粒体相关活性氧（reactive oxygen species）的生成。事实上，即使在闭塞冠状动脉（coronary artery）再通后，通过药理学手段激活整合应激反应仍可保护心肌免受缺血/再灌注损伤，这凸显了其在心肌梗死（myocardial infarction）治疗中的临床价值。综上，本研究结果表明，在缺血性心脏病中，整合应激反应可通过选择性抑制线粒体蛋白质合成并减轻氧化应激（oxidative stress），从而提升细胞存活能力。