2. Academic Validation
  3. Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia

Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia

  • Cell Rep. 2024 May 28;43(5):114237. doi: 10.1016/j.celrep.2024.114237.
Yan Tang 1,  Junru Wu 2,  Xuejing Sun 2,  Shasha Tan 2,  Wenbo Li 3,  Siyu Yin 2,  Lun Liu 2,  Yuanyuan Chen 2,  Yuanyuan Liu 2,  Qian Tan 2,  Youxiang Jiang 2,  Wenjing Yang 2,  Wei Huang 2,  Chunyan Weng 2,  Qing Wu 4,  Yao Lu 2,  Hong Yuan 2,  Qingzhong Xiao 5,  Alex F Chen 6,  Qingbo Xu 7,  Timothy R Billiar 8,  Jingjing Cai 9
Affiliations

Affiliations

  • 1 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.
  • 2 Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China.
  • 3 Department of Plastic and Aesthetic (Burn) Surgery, the Second Xiangya Hospital, Central South University, Changsha 410000, China.
  • 4 Center for High-Performance Computing, Central South University, Changsha 410000, China.
  • 5 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.
  • 6 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.
  • 7 Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 8 Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
  • 9 Clinical Research Center, Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410013, China. Electronic address: caijingjing@csu.edu.cn.
PMID: 38753484 DOI: 10.1016/j.celrep.2024.114237
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.

Keywords

CP: Immunology; cardiolipin; complex II; endotoxin-induced myocardial dysfunction; gasdermin D; mitochondria.

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