mtDNA-STING pathway promotes necroptosis-dependent enterocyte injury in intestinal ischemia reperfusion

Cell Death Dis. 2020 Dec 11;11(12):1050. doi: 10.1038/s41419-020-03239-6.


Intestinal ischemia reperfusion (I/R) injury is the important pathogenesis for acute intestinal barrier disruption. The STING signaling is associated with gut homeostasis and barrier integrity. However, the biological function and regulation of STING signaling in intestinal I/R injury are not yet fully understood. As the ligand of STING signaling, the mitochondrial DNA (mtDNA) has been found to be associated with necroptosis. It still remains unknown whether mtDNA-STING signaling triggers intestinal necroptosis in intestinal I/R injury. We found that circulating RIPK3 was significantly increased and had a positive correlation with markers of enterocyte injury in critically ill patients with intestinal injury. Moreover, the levels of circulating mtDNA were also associated with the levels of circulating RIPK3. To explore the relationship between mtDNA and intestinal necroptosis, mice were treated with the intraperitoneal injection of mtDNA, and necroptosis signaling was remarkably activated and the inhibition of necroptosis alleviated mtDNA-induced intestinal injury. Furthermore, STING knockout mice showed an alleviated intestinal necroptosis. In intestinal I/R injury, mtDNA was released from IECs and necroptosis was also triggered, companied with a significant decrease of RIPK3 in the intestine. STING knockout mice markedly attenuated intestinal necroptosis and intestinal I/R injury. Finally, we found that mtDNA-mediated STING signaling triggered necroptosis through synergistic IFN and TNF-α signaling in primary IECs. Our results indicated that mtDNA-STING signaling can contribute to intestinal I/R injury by promoting IEC necroptosis. STING-mediated both IFN and TNF-α signaling can trigger intestinal nercroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdomen / microbiology
  • Abdomen / pathology
  • Animals
  • Caco-2 Cells
  • Critical Illness
  • DNA, Mitochondrial / genetics*
  • Enterocytes / metabolism*
  • Enterocytes / pathology*
  • Humans
  • Intestines / pathology*
  • Male
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necroptosis / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / blood
  • Reperfusion Injury / blood
  • Reperfusion Injury / genetics
  • Reperfusion Injury / pathology*
  • Signal Transduction


  • DNA, Mitochondrial
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases