Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice

Zhenyu Kang, Mengling Yang, Yue Liu, Yang Gui, Yalan Dong, Haifeng Zhou, Zili Zhang, Mingyue Li, Heng Fan, Zheng Li, Junjie Lu, Junyi Li, Rui Zhu, Chengyu Yin, Boyi Liu, Feng Jiang, Kun Huang, Alexey Sarapultsev, Fangfei Li, Ge Zhang, Ling Zhao, Yanyi Wang, Yunjia Ning, Xiang Cheng, Sarajo K. Mohanta, Changjun Yin, Shanshan Luo (), Andreas J. R. Habenicht () and Desheng Hu ()
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Zhenyu Kang: Huazhong University of Science and Technology
Mengling Yang: Huazhong University of Science and Technology
Yue Liu: Xiyuan Hospital of China academy of Chinese Medical Sciences
Yang Gui: Huazhong University of Science and Technology
Yalan Dong: Huazhong University of Science and Technology
Haifeng Zhou: Huazhong University of Science and Technology
Zili Zhang: Huazhong University of Science and Technology
Mingyue Li: Southeast University
Heng Fan: Huazhong University of Science and Technology
Zheng Li: Huazhong University of Science and Technology
Junjie Lu: Hubei Province
Junyi Li: Huazhong University of Science and Technology
Rui Zhu: Huazhong University of Science and Technology
Chengyu Yin: Huazhong University of Science and Technology
Boyi Liu: Zhejiang Chinese Medical University
Feng Jiang: Tianjin University of Traditional Chinese Medicine
Kun Huang: Huazhong University of Science and Technology
Alexey Sarapultsev: South Ural State University
Fangfei Li: Hong Kong Baptist University
Ge Zhang: Hong Kong Baptist University
Ling Zhao: Huazhong Agricultural University
Yanyi Wang: Chinese Academy of Sciences
Yunjia Ning: Chinese Academy of Sciences
Xiang Cheng: Huazhong University of Science and Technology
Sarajo K. Mohanta: Ludwig-Maximilians-University
Changjun Yin: Ludwig-Maximilians-University
Shanshan Luo: Huazhong University of Science and Technology
Andreas J. R. Habenicht: Ludwig-Maximilians-University
Desheng Hu: Huazhong University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Myocardial ischemia-reperfusion injury (MIRI) is a life-threatening complication of myocardial infarcts, with inner mitochondrial membrane protein dysfunction involved in MIRI-induced heart injury. The role of outer mitochondrial membrane protein mitochondrial antiviral signaling protein (MAVS) is unknown. Here, we show that MAVS expression increases in infarcted myocardium of male wild-type mice. Global MAVS-knock-out or myocardial-specific MAVS knockdown protects male mice from acute and chronic MIRI. MIRI induces double-stranded RNA in affected myocardium, activating intracellular retinoic acid-inducible gene I (RIG-I) signaling, which leads to MAVS aggregation and subsequent non-canonical downstream signaling. MAVS aggregates recruit tumor necrosis factor-associated factor family 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), the activating mitogen-activated protein kinase (MAPK) pathway and apoptosis. MAVS-knock-out reduces c-jun-NH2 terminal kinase (JNK) phosphorylation and apoptosis. JNK inhibition protects against MIRI in wild-type male mice, whereas JNK agonist impairs protection in MAVS-knock-out male mice. MIRI activates RIG-I/MAVS pathway and subsequently triggers the TAK1/TRAF6 complex, leading to the activation of the MAPK/JNK signaling cascade. This sequential activation cascade may serve as a potential therapeutic target for MIRI.

Date: 2025
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DOI: 10.1038/s41467-025-60123-7

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