Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia
Year: 2024
Type: article
Abstract: Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD.
Source: Cell Reports
Authors: Yan Tang, Junru Wu, Xuejing Sun, Shasha Tan, Wenbo Li, Siyu Yin, Lun Liu, Yuanyuan Chen, Yuanyuan Liu, Qian Tan, Youxiang Jiang, Wenjing Yang, Wei Huang, Chunyan Weng, Qing Wu, Yao Lu, Hong Yuan, Qingzhong Xiao, Alex F. Chen, Qingbo Xu, Timothy R. Billiar, Jingjing Cai
Institutions: Central South University, Nanchang University, First Affiliated Hospital of Jiangxi Medical College, Third Xiangya Hospital, First Affiliated Hospital of Nanchang University, Second Xiangya Hospital of Central South University, Queen Mary University of London, William Harvey Research Institute, Shanghai Jiao Tong University, XinHua Hospital, First Affiliated Hospital Zhejiang University, University of Pittsburgh Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
OpenAlex ID: W4396918734