Microvesicle release drives cycles of mitophagy flux disruption and inflammatory amplification in sepsis-induced myocardial dysfunction

作者：Rui Song, Yinrui Ma, Junfang Wan, Shuai Hao, Bing Chen, Yichen Liao, Yingjiao Liao, Yuzhou Xiao, Xi Zhang, Zhaocai Zhang, Shuang Ren, Xuxin Tan, Jiahe Tan, He Huang, Milad Ashrafizadeh, Gautam Sethi, João Conde, Liangming Liu, Chenyang Duan · 发表于：Proceedings of the National Academy of Sciences · 年份：2026 · DOI：10.1073/pnas.2510914123 · 被引用次数：2 · 研究领域：Autophagy in Disease and Therapy、interferon and immune responses、Extracellular vesicles in disease

Sepsis-induced myocardial dysfunction strongly contributes to high mortality in patients with sepsis by exacerbating systemic organ failure; however, the onset and molecular mechanisms driving this vicious cycle remain unclear. Here, we revealed that DRP1-mediated mitochondrial fission and excessive reactive oxygen species (ROS) accumulation are central to the disruption of mitophagy flux and triggering of inflammatory cascades. Using cecal ligation and puncture mice and lipopolysaccharide-treated HL-1 cell models, combined with advanced imaging and molecular analyses, we demonstrated that elevated ROS activates the RIP1/RIP3 pathway, impairing mitophagy flux and promoting the release of microvesicles containing mitochondrial inner membrane components and mitochondrial DNA. These microvesicles amplify inflammatory responses through the cGAS-STING and RIP1/RIP3 pathways, driving the production of damage- and pathogen-associated molecular patterns. This study highlights two interlinked vicious cycles, mitophagy flux disruption and damage- and pathogen-associated molecular pattern amplification, as critical drivers of sepsis-induced myocardial injury, providing therapeutic targets for mitigating inflammatory damage and improving clinical outcomes in patients with sepsis.