NDLI: Blockade of the mitochondrial DNA release ameliorates hepatic ischemia-reperfusion injury through avoiding the activation of cGAS-Sting pathway

Content Provider	Springer Nature : BioMed Central
Author	Xiong, Yi Chen, Jiawen Liang, Wei Li, Kun Huang, Yingqi Song, Jingwen Zhang, Baoyu Qiu, Xiusheng Qiu, Dongbo Zhang, Qi Qin, Yunfei
Abstract	Background Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated. Methods Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models. Results Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization. Conclusions The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.
Related Links	https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-024-05588-8.pdf
Ending Page	16
Page Count	16
Starting Page	1
File Format	HTM / HTML
ISSN	14795876
DOI	10.1186/s12967-024-05588-8
Journal	Journal of Translational Medicine
Issue Number	1
Volume Number	22
Language	English
Publisher	BioMed Central
Publisher Date	2024-08-28
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health cGAS Hepatic ischemia-reperfusion injury Innate immunity mtDNA STING Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	6.3/2023

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