Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes

Abstract

Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissues. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In a further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was the result of PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM. Graphical abstract

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders

“…MtDNA is detected by cGAS, a dsDNA sensor that generates cGAMP that further binds directly to the stimulator of interferon genes (STING), activating the protein kinase tank-binding kinase 1 (TBK1). The activation of TBK1 leads to interferon regulatory factor 3 (IRF3) phosphorylation, translocation into the nucleus and consequent induction of various IFN-stimulated genes [ 101 , 102 , 103 ]. Moreover, TBK1 also activates the NF-κB signalling pathway through phosphorylation, thus increasing the expression of IL-6 and TNF-α.…”

Link between sterile inflammation and cardiovascular diseases: Focus on cGAS-STING pathway in the pathogenesis and therapeutic prospect

“…ELISA, LC-MS, and LC-MS/MS are the main approaches to detect the content of cGAMP in heart or vascular tissues (16,21,27,28). Immunofluorescene staining with dsDNAand qPCR of cytosolic mtDNA are the main approaches to detect the content of cytosolic DNA in heart or vascular tissues (21,(28)(29)(30)(31)(32)(33)(34)(35). Oxidative stress, mitochondrial damage, and mtDNA leakage are considered to be the main reason for generation of cGAMP or accumulation of cytosolic DNA in cardiovascular diseases (16,21,(29)(30)(31)(32)(33)(34)(35).…”

“…Immunofluorescene staining with dsDNAand qPCR of cytosolic mtDNA are the main approaches to detect the content of cytosolic DNA in heart or vascular tissues (21,(28)(29)(30)(31)(32)(33)(34)(35). Oxidative stress, mitochondrial damage, and mtDNA leakage are considered to be the main reason for generation of cGAMP or accumulation of cytosolic DNA in cardiovascular diseases (16,21,(29)(30)(31)(32)(33)(34)(35). Herein, we summarize the studies that have uncovered the increased content of cGAMP or cytoplasmic DNA in cardiovascular diseases (Table 1).…”

“…Hyperlipidemia in diabetic mice caused DNA leakage of myocardial cells to activate cGAS-STING signaling, which led to pyroptosis and induced inflammation, ultimately resulting in myocardial hypertrophy and remodeling (16). Nonetheless, knockdown of Sting gene by AAV9 or pharmacological inhibition of STING effectively alleviated myocardial inflammation and diabetic cardiomyopathy (16,34). In conclusion, it elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation as a new potential therapeutic strategy for the treatment of DCM.…”

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders

“…MtDNA is detected by cGAS, a dsDNA sensor that generates cGAMP that further binds directly to the stimulator of interferon genes (STING) activating the protein kinase tankbinding kinase 1 (TBK1). The activation of TBK1 leads to interferon regulatory factor 3 (IRF3) phosphorylation, translocation into the nucleus and consequent induction of various IFN-stimulated genes [97][98][99]. Moreover, TBK1 also activates the NF-κB signalling pathway through phosphorylation, thus increasing the expression of IL-6 and TNF-α.…”