Mitochondrial Tumor Suppressor 1A Attenuates Myocardial Infarction Injury by Maintaining the Coupling Between Mitochondria and Endoplasmic Reticulum

作者：Yingchao Gong, Xue Lü, Xingchen Wang, Yinfang Wang, Zhida Shen, Yun Gao, Lenan Zhuang, Luyang Yu, Jiawen Chen, Qinfeng Li, Fuyu Qiu, Jun Lin, Yuhang Tao, Chenyang Jiang, Guosheng Fu, Peng Zhang, Dongwu Lai · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.124.069737 · 被引用次数：25 · 研究领域：Mitochondrial Function and Pathology、Cardiac Fibrosis and Remodeling、Congenital heart defects research

BACKGROUND: Pathological cardiac remodeling after myocardial infarction (MI) is a leading cause of heart failure and sudden death. The detailed mechanisms underlying the transition to heart failure after MI are not fully understood. Disruptions in the endoplasmic reticulum (ER)–mitochondria connectivity, along with mitochondrial dysfunction, are substantial contributors to this remodeling process. In this study, we aimed to explore the impact of mitochondrial tumor suppressor 1A (Mtus1A) on cardiac remodeling subsequent to MI and elucidate its regulatory role in ER-mitochondria interactions. METHODS: Single-nucleus RNA sequencing analysis was performed to delineate the expression patterns of mitochondrial tumor suppressor 1 (Mtus1) in human cardiomyocytes under ischemic stress. MI models were induced in mice by left coronary artery ligation and replicated in vitro using primary neonatal rat ventricular myocytes exposed to oxygen glucose deprivation. Cardiac-specific deletion of Mtus1 was achieved by crossing floxed Mtus1 mice with the Myh6-MerCreMer mice. The impact of Mtus1A, a mitochondrial isoform of Mtus1, on cardiac function and the molecular mechanisms were investigated in both in vivo and in vitro settings. Mitochondria-associated ER membranes (MAMs) coupling levels were evaluated by transmission electron microscopy and live-cell imaging. Protein interactions involving Mtus1A were explored through immunoprecipitation–mass spectrometry, coimmunoprecipitation, and proxim...