S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis

  • Cell Death Dis. 2024 Jun 28;15(6):462. doi: 10.1038/s41419-024-06849-6.
Yanghanzhao Wang  1  2  3 ,  Yuxin Shi  1  2  3 ,  Yuwen Shao  1  2  3 ,  Xihua Lu  4 ,  Hao Zhang  5  6  7 ,  Changhong Miao  8  9  10
Affiliations
  • 1. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2. Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
  • 3. Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 4. Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
  • 5. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 6. Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China. [email protected].
  • 7. Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 8. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 9. Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China. [email protected].
  • 10. Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
PMID: 38942784 DOI: 10.1038/s41419-024-06849-6
Abstract

S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell Apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD+-dependent SIRT1 suppression, which induces mitochondrial disorders, including excessive fission and blocked Mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9hi neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.

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