天津医科大学常永生团队的研究认为心肌细胞中RNF10缺乏损害线粒体自噬并驱动病理性肥大。2026年7月15日出版的《中国药理学报》发表了这项成果。

在这项研究中，研究人员观察到心脏RNF10的表达受到多种慢性应激源的诱导，包括衰老、血管紧张素II （Ang II）暴露和肥胖。心脏特异性RNF10基因敲除（RNF10- CKO）小鼠随着年龄增长出现心肌肥大，表现为心肌细胞增大、心肌纤维化加剧和心功能受损。老年RNF10-CKO小鼠表现出心肌细胞活性氧（ROS）水平升高和线粒体膜电位降低。透射电镜显示线粒体变圆、基质扩张和嵴紊乱。

同样，与对照小鼠相比，暴露于Ang II的RNF10-CKO小鼠表现出心肌细胞肥大、纤维化增加和心功能障碍，并伴有线粒体膜电位去极化、ROS积累和线粒体形态异常，与老年RNF10-CKO小鼠相当。在机制上，慢性应激源上调RNF10表达，随后介导线粒体外膜蛋白丝裂原2 （MFN2）的K63连锁多泛素化。这种修饰稳定了线粒体上的MFN2，促进了Parkin的募集。线粒体中积累的Parkin进一步促进了自噬衔接子序列体1 （SQSTM1/p62）的自动募集，导致LC3-II脂化增加，线粒体自噬开始。值得注意的是，RNF10介导的线粒体自噬依赖于MFN2。

然而，RNF10的作用是独立于PINK1的。本研究确定RNF10是心脏有丝分裂的关键调节因子，表明靶向心脏RNF10可能是治疗心脏病变的一种治疗策略。

研究人员表示，线粒体自噬介导的线粒体质量控制对正常的心脏生理至关重要。

附：英文原文

Title: RNF10 deficiency in cardiomyocytes impairs mitophagy and drives pathological hypertrophy

Author: Song, Jia-ni, Qiu, Tong-tong, Zhang, Lei, Huang, Jin-can, Zhang, Yu-jie, Zhang, Yin-liang, Chang, Yong-sheng

Issue&Volume: 2026-07-15

Abstract: Mitophagy-mediated mitochondrial quality control is essential for normal cardiac physiology. In this study, we observed that cardiac RNF10 expression was induced by multiple chronic stressors, including aging, angiotensin II (Ang II) exposure, and obesity. Cardiac-specific RNF10 knockout (RNF10-CKO) mice developed cardiac hypertrophy with aging, characterized by cardiomyocyte enlargement, exacerbated myocardial fibrosis, and impaired cardiac function. Aged RNF10-CKO mice exhibited elevated reactive oxygen species (ROS) levels and reduced mitochondrial membrane potential in cardiomyocytes. Transmission electron microscopy revealed mitochondrial rounding, matrix expansion, and cristae disorganization. Similarly, compared with control mice, Ang II-exposed RNF10-CKO mice exhibited cardiomyocyte hypertrophy, increased fibrosis, and cardiac dysfunction, accompanied by mitochondrial membrane potential depolarization, ROS accumulation, and mitochondrial morphological abnormalities equivalent to those in aged RNF10-CKO mice. Mechanistically, chronic stressors upregulated RNF10 expression, which subsequently mediated the K63-linked polyubiquitination of the mitochondrial outer membrane protein mitofusin 2 (MFN2). This modification stabilized MFN2 on mitochondria and facilitated Parkin recruitment. The accumulated Parkin in mitochondria further promoted the robust recruitment of the autophagy adaptor sequestosome 1 (SQSTM1/p62), leading to increased LC3-II lipidation and the initiation of mitophagy. Notably, this RNF10-mediated mitophagy is dependent on MFN2. However, the effects of RNF10 are independent of those of PINK1. This study identifies RNF10 as a critical regulator of cardiac mitophagy, suggesting that targeting cardiac RNF10 may represent a therapeutic strategy for treating cardiac pathologies.

DOI: 10.1038/s41401-026-01838-1

Source: https://www.nature.com/articles/s41401-026-01838-1