Song Shuai, Zhang Xiaokai, Huang Zihang, Pei Zhiqiang, Zeng Linqi, Cai Fengze, Wang Tongyao, Li Mohan, Liu Chenyan, Song Yining, Guo Jiahao, Lu Hao, Weng Xinyu, Shen Li, Zhang Xiaochun, Cai Xingxing, Sun Aijun, Ge Junbo
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China.
Adv Sci (Weinh). 2025 Jun 23:e08673. doi: 10.1002/advs.202508673.
Mitochondrial dysfunction is related to etiopathogenesis and progression of heart failure (HF). The underlying molecular mechanisms are not fully understood. Transcription factor FOXM1 plays an essential role in cardiovascular development. The present study explores its role in mitochondrial bioenergetics in postmitotic cardiomyocytes (CMs). FOXM1 is significantly upregulated in ischemic heart tissues from humans, mice, and pigs. CM-specific Foxm1-knockout mice exhibit dilated cardiomyopathy features associated with mitochondrial dysfunction. Transcriptomic and proteomic profiling of Foxm1-knockout mice reveal robust, specific downregulation of gene programs important for mitochondrial energetics and homeostasis. Analysis of proteome and ubiquitinome data reveal that FOXM1 deficiency in CMs promotes LKB1 ubiquitination and impairs the AMPK signaling and energy metabolism pathways. Bioinformatics analysis identifies that E3 ligase MKRN1 promotes the K48-linked ubiquitination of LKB1 on Lys146, which in turn, inhibits the AMPK signaling pathway and impairs energy homeostasis in mice with HF. CM-specific Mkrn1 knockout ameliorates cardiac dysfunction by rejuvenating the impaired mitochondrial bioenergetics induced by FOXM1 deficiency. FOXM1 overexpression preserves mitochondrial bioenergetics and protects against myocardial I/R injury in both rodent and porcine models. In conclusion, FOXM1 is actively involved in mitochondrial bioenergetics during HF. FOXM1 may be a potential promising therapeutic target for myocardial I/R injury and HF.
线粒体功能障碍与心力衰竭（HF）的病因及进展相关。其潜在的分子机制尚未完全明确。转录因子FOXM1在心血管发育中起关键作用。本研究探讨其在有丝分裂后心肌细胞（CMs）线粒体生物能量学中的作用。在人类、小鼠和猪的缺血性心脏组织中，FOXM1显著上调。CM特异性Foxm1基因敲除小鼠表现出与线粒体功能障碍相关的扩张型心肌病特征。对Foxm1基因敲除小鼠的转录组和蛋白质组分析显示，对线粒体能量学和稳态至关重要的基因程序出现显著、特异性下调。蛋白质组和泛素组数据分析表明，CMs中FOXM1缺乏会促进LKB1泛素化，损害AMPK信号通路和能量代谢途径。生物信息学分析确定E3连接酶MKRN1促进LKB1第146位赖氨酸的K48连接泛素化，进而抑制AMPK信号通路，损害HF小鼠的能量稳态。CM特异性Mkrn1基因敲除通过恢复由FOXM1缺乏引起的受损线粒体生物能量学来改善心脏功能障碍。在啮齿动物和猪模型中，FOXM1过表达可维持线粒体生物能量学并保护心肌免受I/R损伤。总之，FOXM1在HF期间积极参与线粒体生物能量学。FOXM1可能是心肌I/R损伤和HF的一个潜在有前景的治疗靶点。
