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

Cell Reports (May 2024)

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

Journal volume & issue: Vol. 43, no. 5
p. 114237

Abstract

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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.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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