RIPK3-driven phosphorylation of MFN2 orchestrates endoplasmic reticulum-mitochondria interaction and cardiomyocyte stress responses

作者：Yanru Wang, Tao Xu, Qing Li, Lin Ye, Peiyan Wang, P. Wang, Yihan Song, Xiang Ao, Jianxun Wang, Wei Ding · 发表于：Redox Biology · 年份：2026 · DOI：10.1016/j.redox.2026.104006 · 被引用次数：8 · 研究领域：Mitochondrial Function and Pathology、Cell death mechanisms and regulation、Endoplasmic Reticulum Stress and Disease

Recent studies have demonstrated that necroptosis is one of the main forms of cardiomyocyte death in heart diseases. However, the crosstalk between the death-receptor necroptosis pathway and the mitochondrial necroptosis pathway remains largely unknown. It has been reported that Mitofusin 2 (MFN2) can promote myocardial injury by inducing Endoplasmic Reticulum (ER)-mitochondria interaction. The purpose of this study was to investigate whether MFN2 promotes cardiac necroptosis and myocardial ischemia/reperfusion (I/R) injury by regulating ER-mitochondrial interactions, and whether this function of MFN2 can be regulated by the death-receptor necroptosis pathway. Myocardial necroptosis was induced by H 2 O 2 in H9c2 cardiomyocytes in vitro and through left anterior descending (LAD) ligation and subsequent reperfusion in C57/BL6 mice in vivo. ER-mitochondria interaction was detected by immunofluorescence. Calcium levels were analyzed by Rhod-AM staining. The interaction between MFN2 and Receptor-interacting protein kinase 3 (RIPK3) was explored by co-immunoprecipitation and immunofluorescence. The phosphorylation site of MFN2 was examined and measured via mass spectrometry analysis. Additionally, a customized MFN2 phosphorylation-specific antibody was used to detect the role of the Threonine 130 site of MFN2 in myocardial necroptosis. In vivo, MFN2 cardiac-specific knockout mice were constructed to further explore the effect of MFN2 on myocardial I/R injury and necroptosis. Our r...