RAB7通过促进非规范TUFM有丝分裂途径预防缺血性心力衰竭。

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-06-09 eCollection Date: 2025-01-01 DOI:10.7150/thno.104124
Yuling Sun, Wei Wang, Mingyan Li, Wen Guan, Zhimin Gao, Luping Wang, Guanlan Lou, Ao Shen, Jiangbin Wu, Xiyong Yu, Panxia Wang, Xiaoqian Wu
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引用次数: 0

摘要

理由:心肌细胞凋亡是缺血性心力衰竭(IHF)进展的关键因素。虽然内溶体-溶酶体系统控制细胞稳态,但其主要调节因子RAB7在心脏病理生理中的功能意义尚不清楚。方法:采用心肌细胞特异性RAB7基因敲除小鼠冠状动脉左前降支结扎心肌梗死模型和腺相关病毒介导的RAB7过表达模型,通过超声心动图和病理生理评估心功能和不良重构。用mt-Keima小鼠和共聚焦成像定量测定线粒体自噬通量。通过免疫沉淀-质谱(IP-MS)分析和分子实验验证对其分子机制进行了剖析。结果:缺血心肌中RAB7表达降低。心肌细胞特异性RAB7消融加重,而RAB7过表达减弱心肌梗死后心功能障碍和适应性重构不良。在体外和体内实验中,RAB7增强了缺血应激下受损线粒体的自噬清除,减少心肌细胞凋亡。在机制上,线粒体翻译延伸因子TUFM被确定为RAB7的新效应物。RAB7促进TUFM和LC3向受损线粒体募集,从而增强线粒体自噬。TUFM敲除显著降低RAB7对线粒体自噬和心肌细胞存活的保护作用。最后,给药ML-098(一种化学RAB7激活剂)可促进小鼠的线粒体自噬并减缓IHF进展。结论:我们通过tufm介导的机制组装确定RAB7是一种新的心脏保护性有丝分裂协调者。RAB7-TUFM轴代表了IHF的治疗靶点,值得进一步的临床评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
RAB7 protects against ischemic heart failure via promoting non-canonical TUFM mitophagy pathway.

Rationale: Cardiomyocyte apoptosis critically contributes to ischemic heart failure (IHF) progression. While the endosome-lysosome system governs cellular homeostasis, the functional significance of its master regulator RAB7 in cardiac pathophysiology remains unexplored. Methods: Using myocardial infarction (MI) models via left anterior descending coronary artery ligation in cardiomyocyte-specific RAB7 knockout mice and adeno-associated virus-mediated RAB7 overexpression models, we assessed cardiac function and adverse remodeling through echocardiography and pathophysiological assessment. Mitophagy flux was quantified using mt-Keima mice and confocal imaging. Molecular mechanisms were dissected through immunoprecipitation coupled with mass spectrometry (IP-MS) analysis and molecular experiment validation. Results: RAB7 expression decreased in ischemic myocardium. Cardiomyocyte-specific RAB7 ablation exacerbated while RAB7 overexpression attenuated post-MI cardiac dysfunction and maladaptive remodeling. RAB7 enhanced mitophagic clearance of damaged mitochondria, reducing cardiomyocyte apoptosis under ischemic stress both in vitro and in vivo. Mechanistically, TUFM, a mitochondrial translation elongation factor, was identified as a novel effector of RAB7. RAB7 facilitated the recruitment of TUFM and LC3 to damaged mitochondria, thereby enhancing mitophagy. TUFM knockdown significantly diminished the protective effects of RAB7 on mitophagy and cardiomyocyte survival. Finally, administration of ML-098, a chemical RAB7 activator, promoted mitophagy and mitigated IHF progression in mice. Conclusion: We identify RAB7 as a novel coordinator of cardioprotective mitophagy through TUFM-mediated machinery assembly. The RAB7-TUFM axis represents a therapeutic target for IHF that warrants further clinical evaluation.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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