AI Article Synopsis
- S100a8/a9 is a calcium-binding protein released by neutrophils that plays a significant role in inflammatory diseases and has been linked to endothelial cell death during sepsis.
- High levels of S100a8/a9 lead to reduced Ndufa3 expression in mitochondrial complex I, which causes mitochondrial dysfunction and triggers cell death processes in endothelial cells.
- Research shows that S100A8/A9 levels in neutrophils correlate with circulating endothelial cell counts, indicating endothelial damage, and S100A8 is identified as a risk factor for poor outcomes in sepsis patients.
Article 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/A9 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213914 | PMC |
| http://dx.doi.org/10.1038/s41419-024-06849-6 | DOI Listing |
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