Microvesicle release drives cycles of mitophagy flux disruption and inflammatory amplification in sepsis-induced myocardial dysfunction
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Rui Song
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Yinrui Ma
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Junfang Wan
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Shuai Hao
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry
Bing Chen
Yichen Liao
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Yingjiao Liao
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Yuzhou Xiao
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Xi Zhang
Zhaocai Zhang
Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine
Shuang Ren
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Xuxin Tan
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University
Jiahe Tan
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University
He Huang
Milad Ashrafizadeh
Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences
Gautam Sethi
Department of Pharmacology and National University of Singapore Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore
João Conde
Liangming Liu
State Key Laboratory of Trauma and Chemical Poisoning, Department of Shock and Transfusion, Army Medical Center, Army Medical University
Chenyang Duan
Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University