FMO2 Prevents Pathological Cardiac Hypertrophy by Maintaining the ER-Mitochondria Association Through Interaction With IP3R2-Grp75-VDAC1

作者：Changchen Xiao, Chao Wang, Jingyi Wang, Jingyi Wang, Xianpeng Wu, Changle Ke, Jinliang Nan, Hao Ding, Yinghui Xu, Yanna Shi, Jing Zhao, Cheng Ni, Qingnian Liu, Jiamin Li, Shuyuan Sheng, Hua Chen, Jiayue Cai, Tonghui Zhao, Jinghai Chen, Qiming Sun, Bin Zhou, Jianan Wang, Jianan Wang, Wei Zhu, Xinyang Hu · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.124.072661 · 被引用次数：23 · 研究领域：Mitochondrial Function and Pathology、Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease

BACKGROUND: Cardiac hypertrophy, as an important pathological change, contributes to heart failure. Recent studies indicate that the mitochondria-associated endoplasmic reticulum membranes (MAMs) play key roles in this pathological process. However, the molecular mechanism remains unclear. This study aims to elucidate the effects and mechanisms of MAM-resident FMO2 (flavin-containing monooxygenase 2) in cardiac hypertrophy and heart failure. METHODS: We performed bulk RNA-sequencing analysis using heart tissue from patients with cardiac hypertrophy and carried out MAM-targeted mass spectrometry analysis using heart tissue from a mouse model of pathological cardiac hypertrophy. In vitro cell culture using neonatal rat cardiomyocytes was used to study how MAMs formation affected cardiomyocyte functions. By generating different genetic mouse models combined with using adeno-associated virus 9 under the cardiac troponin T promoter techniques, we further investigated and confirmed the effects of MAM structure changes on cardiac hypertrophy. RESULTS: We detected an unexpected component of MAMs structure, which was the FMO2, an endoplasmic reticulum–resident protein. FMO2 levels decreased during pathological cardiac hypertrophy. The deletion and overexpression of FMO2 can either worsen or prevent the pathological heart failure progression in vivo, respectively. Our data further demonstrated that FMO2 localizes to MAM structure, where it binds to inositol 1,4,5-trisphosphate type 2 r...