Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia
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
Affiliations
Yan Tang
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China; Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
Junru Wu
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Xuejing Sun
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Shasha Tan
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Wenbo Li
Department of Plastic and Aesthetic (Burn) Surgery, the Second Xiangya Hospital, Central South University, Changsha 410000, China
Siyu Yin
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Lun Liu
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Yuanyuan Chen
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Yuanyuan Liu
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Qian Tan
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Youxiang Jiang
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Wenjing Yang
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Wei Huang
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Chunyan Weng
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Qing Wu
Center for High-Performance Computing, Central South University, Changsha 410000, China
Yao Lu
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Hong Yuan
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Qingzhong Xiao
Centre for Clinical Pharmacology, William Harvey Research Institute, Barts, and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Alex F. Chen
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China; Department of Cardiology, Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, China
Qingbo Xu
Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Timothy R. Billiar
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Jingjing Cai
Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China; Corresponding author
Summary: 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.
