Shen Yang, Gao Xin, Xiang Ying, Zhou Hao, Zhu Hang, Wu Qiang, Liu Jinfeng
Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
Department of Cardiology, School of Medicine, South China University of Technology, Guangzhou 510006, China.
Int J Med Sci. 2025 Jan 1;22(1):188-196. doi: 10.7150/ijms.100523. eCollection 2025.
This study investigates the role of Fundc1 in cardiac protection under high-altitude hypoxic conditions and elucidates its underlying molecular mechanisms. Using cardiomyocyte-specific knockout ( ) mice, we demonstrated that deficiency exacerbates cardiac dysfunction under simulated high-altitude hypoxia, manifesting as impaired systolic and diastolic function. Mechanistically, we identified that Fundc1 regulates cardiac function through the mitochondrial unfolded protein response (mito-UPR) pathway. deficiency led to significant downregulation of multiple mito-UPR-related factors, including ATF5, Chop, and PITRM1. Further investigation revealed that Fundc1 deficiency results in increased cardiomyocyte apoptosis, calcium dysregulation, reduced cell viability, and impaired mitochondrial function, characterized by decreased ATP production, reduced membrane potential, and increased ROS production. Notably, activation of mito-UPR with oligomycin significantly ameliorated these cardiac abnormalities in Fundc1-deficient mice. We identified ATF5 as a key downstream effector of Fundc1, as ATF5 overexpression effectively reversed cardiac dysfunction and restored mito-UPR-related gene expression in Fundc1-deficient hearts. Additionally, we discovered that Fundc1-mediated cardioprotection involves regulation of mitophagy, where its activation improved cardiac function and mitochondrial homeostasis in Fundc1-deficient mice. Our findings reveal a novel Fundc1-ATF5-mito-UPR axis in cardioprotection against high-altitude hypoxia and highlight the crucial role of mitophagy in this protective mechanism, providing new insights into potential therapeutic strategies for high-altitude heart disease.
本研究调查了Fundc1在高海拔缺氧条件下心脏保护中的作用，并阐明其潜在的分子机制。利用心肌细胞特异性敲除（ ）小鼠，我们证明了Fundc1缺陷在模拟高海拔缺氧条件下会加剧心脏功能障碍，表现为收缩和舒张功能受损。机制上，我们发现Fundc1通过线粒体未折叠蛋白反应（mito-UPR）途径调节心脏功能。Fundc1缺陷导致多个mito-UPR相关因子显著下调，包括ATF5、Chop和PITRM1。进一步研究表明，Fundc1缺陷导致心肌细胞凋亡增加、钙调节异常、细胞活力降低和线粒体功能受损，其特征是ATP生成减少、膜电位降低和活性氧生成增加。值得注意的是，用寡霉素激活mito-UPR可显著改善Fundc1缺陷小鼠的这些心脏异常。我们确定ATF5是Fundc1的关键下游效应因子，因为ATF5过表达可有效逆转Fundc1缺陷心脏的心脏功能障碍并恢复mito-UPR相关基因表达。此外，我们发现Fundc1介导的心脏保护涉及对线粒体自噬的调节，其激活改善了Fundc1缺陷小鼠的心脏功能和线粒体稳态。我们的研究结果揭示了在对抗高海拔缺氧的心脏保护中一个新的Fundc1-ATF5-mito-UPR轴，并突出了线粒体自噬在这一保护机制中的关键作用，为高海拔心脏病的潜在治疗策略提供了新的见解。
