Oxidized mitochondrial DNA activates the cGAS-STING pathway in the neuronal intrinsic immune system after brain ischemia-reperfusion injury

Qingsheng Li; Lingfei Yang; Kaixin Wang; Ziyi Chen; Huimin Liu; Xuan Yang; Yudi Xu; Yufei Chen; Zhe Gong; Yanjie Jia

doi:10.1016/j.neurot.2024.e00368

Oxidized mitochondrial DNA activates the cGAS-STING pathway in the neuronal intrinsic immune system after brain ischemia-reperfusion injury

Neurotherapeutics. 2024 Apr 29:e00368. doi: 10.1016/j.neurot.2024.e00368. Online ahead of print.

Authors

Qingsheng Li¹, Lingfei Yang¹, Kaixin Wang², Ziyi Chen³, Huimin Liu², Xuan Yang², Yudi Xu², Yufei Chen², Zhe Gong⁴, Yanjie Jia⁵

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000 Henan, China.
² Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000 Henan, China.
⁴ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: gongzhe1415@163.com.
⁵ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: jiayanjie1971@zzu.edu.cn.

PMID: 38688786
DOI: 10.1016/j.neurot.2024.e00368

Abstract

In the context of stroke and revascularization therapy, brain ischemia-reperfusion injury is a significant challenge that leads to oxidative stress and inflammation. Central to the cell's intrinsic immunity is the cGAS-STING pathway, which is typically activated by unusual DNA structures. The involvement of oxidized mitochondrial DNA (ox-mtDNA)-an oxidative stress byproduct-in this type of neurological damage has not been fully explored. This study is among the first to examine the effect of ox-mtDNA on the innate immunity of neurons following ischemia-reperfusion injury. Using a rat model of transient middle cerebral artery occlusion and a cellular model of oxygen-glucose deprivation/reoxygenation, we have discovered that ox-mtDNA activates the cGAS-STING pathway in neurons. Importantly, pharmacologically limiting the release of ox-mtDNA into the cytoplasm reduces inflammation and improves neurological functions. Our findings suggest that targeting ox-mtDNA release may be a valuable strategy to attenuate brain ischemia-reperfusion injury following revascularization therapy for acute ischemic stroke.

Keywords: Brain ischemia-reperfusion injury; Inflammation; Neuronal immunity; Ox-mtDNA; cGAS-STING pathway.