Decreased MFN2 activates the cGAS-STING pathway in diabetic myocardial ischaemia-reperfusion by triggering the release of mitochondrial DNA.
Decreased MFN2 activates the cGAS-STING pathway in diabetic myocardial ischaemia-reperfusion by triggering the release of mitochondrial DNA.
复制标题
减少的MFN2通过触发线粒体DNA的释放激活糖尿病心肌缺血-再灌注中的cGAS-STING通路。
DOI：
10.1186/s12964-023-01216-y
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发表时间：
2023-08-03
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影响因子：
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中科院分区：
文献类型：
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The cause of aggravation of diabetic myocardial damage is yet to be elucidated; damage to mitochondrial function has been a longstanding focus of research. During diabetic myocardial ischaemia–reperfusion (MI/R), it remains unclear whether reduced mitochondrial fusion exacerbates myocardial injury by generating free damaged mitochondrial DNA (mitoDNA) and activating the cGAS-STING pathway. In this study, a mouse model of diabetes was established (by feeding mice a high-fat diet (HFD) plus a low dose of streptozotocin (STZ)), a MI/R model was established by cardiac ischaemia for 2 h and reperfusion for 30 min, and a cellular model of glycolipid toxicity induced by high glucose (HG) and palmitic acid (PA) was established in H9C2 cells. We observed that altered mitochondrial dynamics during diabetic MI/R led to increased mitoDNA in the cytosol, activation of the cGAS-STING pathway, and phosphorylation of the downstream targets TBK1 and IRF3. In the cellular model we found that cytosolic mitoDNA was the result of reduced mitochondrial fusion induced by HG and PA, which also resulted in cGAS-STING signalling and activation of downstream targets. Moreover, inhibition of STING by H-151 significantly ameliorated myocardial injury induced by MFN2 knockdown in both the cell and mouse models. The use of a fat-soluble antioxidant CoQ10 improved cardiac function in the mouse models. Our study elucidated the critical role of cGAS-STING activation, triggered by increased cytosolic mitoDNA due to decreased mitochondrial fusion, in the pathogenesis of diabetic MI/R injury. This provides preclinical insights for the treatment of diabetic MI/R injury. Video Abstract The online version contains supplementary material available at 10.1186/s12964-023-01216-y.
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影响因子：
6.1
作者：
通讯作者：
--
影响因子：
3.7
作者：
Alehagen U;Aaseth J;Alexander J;Johansson P
通讯作者：
Johansson P
影响因子：
9.2
作者：
Chang, Xing;Liu, Ruxiu;Li, Ruibing;Peng, Youyou;Zhu, Pingjun;Zhou, Hao
通讯作者：
Zhou, Hao
抑制动力相关蛋白 1 可预防糖尿病小鼠心肌缺血再灌注损伤
影响因子：
9.3
作者：
Ding M;Dong Q;Liu Z;Liu Z;Qu Y;Li X;Huo C;Jia X;Fu F;Wang X
通讯作者：
Wang X
影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC