Li Runjing, Gao Feng, Chen Yunan, Zhao Jiamin, Shi Rui, Li Man, Zuo Zhenzi, Chang Pan, De Dema, Chen Lin, Fu Feng, Ding Mingge
Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, China.
Department of Cardiovascular Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, China.
Redox Biol. 2025 Jun 28;85:103745. doi: 10.1016/j.redox.2025.103745.
Increasing evidence has implicated the important role of mitochondrial morphofunctional defects in pathological myocardial hypertrophy and heart failure. Deubiquitinating enzymes (DUBs) are involved in protein stability maintenance and regulate multiple cellular processes, while it remains largely unclear whether DUBs participate in the maintenance of mitochondrial morphofunction. The aim of this study was to investigate the possible link between DUBs and abnormal mitochondrial morphofunction in pressure overload-induced pathological cardiac hypertrophy and explore the underlying molecular mechanism. RNA sequencing results showed that ubiquitin-mediated proteolysis was markedly enriched in pressure overload-induced hypertrophied and failing myocardium, and USP10 was identified as the most significantly downregulated gene among them and correlated with heart failure severity in human heart samples. Restoration of USP10 mitigates cardiac hypertrophy and dysfunction as well as abnormal mitochondrial morphofunction in vitro and in vivo. Immunoprecipitation and mass spectrometry analysis mechanistically revealed that USP10 directly interacted with Mfn2 (a mitochondrial outer membrane protein). Interestingly, the interaction between Mfn2 and USP10 occurred in cytoplasm but not on mitochondria. His-679 in the UCH domain of USP10 exerted deubiquitination to maintain the stability of the Mfn2 by removing the K11/K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining mitochondrial function and homeostasis. Knockdown or knockout of Mfn2 largely eliminated the cardioprotection of USP10. Additionally, reduced USP10 expression in hypertrophied myocardium was induced by impaired translation of Yy1. Together, our findings provide a USP10-modulated mitochondrial homeostasis mechanism that enhances the stability of cytoplasmic Mfn2 before its translocation to mitochondria. USP10 may represent a novel therapeutic target for combating pressure overstress-induced cardiac hypertrophy and heart failure.
越来越多的证据表明线粒体形态功能缺陷在病理性心肌肥大和心力衰竭中起重要作用。去泛素化酶（DUBs）参与维持蛋白质稳定性并调节多种细胞过程，然而DUBs是否参与线粒体形态功能的维持在很大程度上仍不清楚。本研究的目的是探讨DUBs与压力超负荷诱导的病理性心脏肥大中线粒体形态功能异常之间的可能联系，并探索其潜在的分子机制。RNA测序结果显示，泛素介导的蛋白水解在压力超负荷诱导的肥大和衰竭心肌中显著富集，USP10被确定为其中下调最显著的基因，并且与人心脏样本中的心力衰竭严重程度相关。在体外和体内恢复USP10可减轻心脏肥大、功能障碍以及线粒体形态功能异常。免疫沉淀和质谱分析从机制上揭示了USP10直接与Mfn2（一种线粒体外膜蛋白）相互作用。有趣的是，Mfn2与USP10之间的相互作用发生在细胞质中而非线粒体上。USP10的UCH结构域中的His-679通过去除K11/K48泛素链并防止蛋白酶体途径降解来发挥去泛素化作用以维持Mfn2的稳定性，从而维持线粒体功能和稳态。敲低或敲除Mfn2在很大程度上消除了USP10的心脏保护作用。此外，Yy1翻译受损诱导肥大心肌中USP10表达降低。总之，我们的研究结果提供了一种USP10调节的线粒体稳态机制，该机制在细胞质Mfn2转运至线粒体之前增强其稳定性。USP10可能代表了对抗压力超负荷诱导的心脏肥大和心力衰竭的新型治疗靶点。
