Yuan Tianyou, Zhou Changzuan, Long Yifan, Chen Xiaoqiang, Gao Longzhe, Li Ya, Chen Songwen, Lu Xiaofeng, Xu Juan, Wu Xiaoyu, Zhou Genqing, Liu Shaowen, Yang Wenyi, Wei Yong, Cai Lidong
Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China.
Department of Cardiology, Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, China.
Cell Mol Life Sci. 2025 Sep 2;82(1):332. doi: 10.1007/s00018-025-05839-x.
Mitochondrial dysfunction is increasingly recognized as a pivotal driver of cardiomyocyte apoptosis and cardiac deterioration following myocardial infarction (MI). This study identifies a significant upregulation of DDX60 in cardiomyocytes under hypoxic conditions. Elevated DDX60 levels enhance mitochondrial function and attenuate cardiomyocyte apoptosis in vitro, whereas its knockdown induces the opposite effects. In vivo, cardiomyocyte-specific DDX60 knockout markedly exacerbates mitochondrial dysfunction and apoptosis, accelerating post-MI cardiac remodeling and functional decline. Furthermore, we found that Arl2 knockdown partially negates the protective effects of DDX60 overexpression on ATP production and apoptosis. Conversely, adeno-associated virus-9 (AAV9)-mediated Arl2 overexpression partially restores cardiac function, reduces infarct size, and rescues mitochondrial integrity in DDX60 CKO mice post-MI. Mechanistically, DDX60 forms a translational complex with eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) that enhances Arl2 mRNA translation, a process essential for mitochondrial homeostasis. Collectively, these findings establish DDX60 as a key regulator of cardioprotection post-MI by enhancing Arl2 translation, highlighting its potential as a therapeutic target for ischemic heart disease.
线粒体功能障碍日益被认为是心肌梗死（MI）后心肌细胞凋亡和心脏恶化的关键驱动因素。本研究发现缺氧条件下心肌细胞中DDX60显著上调。体外实验中，升高的DDX60水平增强线粒体功能并减轻心肌细胞凋亡，而敲低DDX60则产生相反的效果。在体内，心肌细胞特异性DDX60基因敲除显著加剧线粒体功能障碍和凋亡，加速MI后心脏重塑和功能衰退。此外，我们发现敲低Arl2可部分抵消DDX60过表达对ATP产生和凋亡的保护作用。相反，腺相关病毒9（AAV9）介导的Arl2过表达可部分恢复DDX60基因敲除小鼠MI后的心脏功能，减小梗死面积，并挽救线粒体完整性。机制上，DDX60与真核翻译起始因子4γ1（EIF4G1）形成翻译复合物，增强Arl2 mRNA翻译，这是线粒体稳态的关键过程。总之，这些发现表明DDX60通过增强Arl2翻译成为MI后心脏保护的关键调节因子，突出了其作为缺血性心脏病治疗靶点的潜力。
