Although endoplasmic reticulum (ER) unfolded protein response (UPR^ER) is well known, mitochondrial unfolded protein response (UPR^mt) has not been recognized in alveolar epithelial cells. Furthermore, ER stress and mitochondrial dysfunction are frequently encountered in alveolar epithelial cells from an array of lung disorders. However, these two scenarios have been often regarded as separate mechanisms contributing to the pathogeneses. It is unclear whether there is interplay between these two phenomena or an integrator that couples these two signaling cascades in the stressed alveolar epithelial cells from those pathologies. In this study, we defined UPR^mt in alveolar epithelial cells and identified ATF4 (activating transcription factor 4), but not ATF5, as the key regulator of UPR^mt. We found that UPR^ER led to UPR^mt and mitochondrial dysfunction in an ATF4-dependent manner. In contrast, mitochondrial stresses did not activate UPR^ER. We found that alveolar epithelial ATF4 and UPR^mt were induced in aged mice with experimental pulmonary fibrosis as well as in patients with idiopathic pulmonary fibrosis. Finally, we found that the inducible expression of ATF4 in mouse alveolar epithelial cells aggravated pulmonary UPR^mt, lung inflammation, body weight loss, and death upon bleomycin-induced lung injury. In conclusion, ER stress induces ATF4-dependent UPR^mt and mitochondrial dysfunction, indicating a novel mechanism by which ER stress contributes to the pathogeneses of a variety of pulmonary disorders.

尽管内质网 (ER) 未折叠蛋白反应 (UPR ^ER ) 是众所周知的，但在肺泡上皮细胞中尚未发现线粒体未折叠蛋白反应 (UPR ^{mt )。}此外，在一系列肺部疾病的肺泡上皮细胞中经常遇到 ER 应激和线粒体功能障碍。然而，这两种情况通常被认为是导致发病机制的独立机制。目前尚不清楚这两种现象之间是否存在相互作用，或者是否存在将来自这些病理的受压肺泡上皮细胞中的这两种信号级联耦合的整合子。在本研究中，我们定义了 UPR ^mt在肺泡上皮细胞中，鉴定出 ATF4（激活转录因子 4），而不是 ATF5，作为 UPR ^mt的关键调节因子。我们发现 UPR ^ER以 ATF4 依赖的方式导致 UPR ^mt和线粒体功能障碍。相反，线粒体应激并未激活 UPR ^ER。我们发现在患有实验性肺纤维化的老年小鼠以及患有特发性肺纤维化的患者中诱导了肺泡上皮 ATF4 和 UPR ^{mt 。}最后，我们发现ATF4在小鼠肺泡上皮细胞中的诱导表达加重了肺UPR ^mt、肺部炎症、体重减轻和博莱霉素引起的肺损伤后死亡。总之，ER 应激诱导 ATF4 依赖性 UPR ^mt和线粒体功能障碍，表明 ER 应激促成多种肺部疾病发病机制的新机制。