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 XuTimothy R. Billiar, Jingjing Cai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number114237
JournalCell Reports
Volume43
Issue number5
DOIs
StatePublished - 28 May 2024
Externally publishedYes

Keywords

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

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