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Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury.

ABSTRACT: The STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.

SUBMITTER: Liu Q

PROVIDER: S-EPMC8254453 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury.

Liu Qinjie Q Wu Jie J Zhang Xufei X Li Xuanheng X Wu Xiuwen X Zhao Yun Y Ren Jianan J

Cell death & disease 20210703 7

The STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are ...[more]

PMID: 34218252

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Project description:The objective of this study was to interrogate the link between mitochondrial dysfunction and mitochondrial-specific autophagy in skeletal muscle. C57BL/6J mice were used to establish a time course of mitochondrial function and autophagy induction after fatigue (n = 12), eccentric contraction-induced injury (n = 20), or traumatic freeze injury (FI, n = 28); only FI resulted in a combination of mitochondrial dysfunction, i.e., decreased mitochondrial respiration, and autophagy induction. Moving forward, we tested the hypothesis that mitochondrial-specific autophagy is important for the timely recovery of mitochondrial function after FI. Following FI, there is a significant increase in several mitochondrial-specific autophagy-related protein contents including dynamin-related protein 1 (Drp1), BCL1 interacting protein (BNIP3), Pink1, and Parkin (~2-fold, P < 0.02). Also, mitochondrial-enriched fractions from FI muscles showed microtubule-associated protein light chain B1 (LC3)II colocalization suggesting autophagosome assembly around the damaged mitochondrial. Unc-51 like autophagy activating kinase (Ulk1) is considered necessary for mitochondrial-specific autophagy and herein we utilized a mouse model with Ulk1 deficiency in adult skeletal muscle (myogenin-Cre). While Ulk1 knockouts had contractile weakness compared with littermate controls (-27%, P < 0.02), the recovery of mitochondrial function was not different, and this may be due in part to a partial rescue of Ulk1 protein content within the regenerating muscle tissue of knockouts from differentiated satellite cells in which Ulk1 was not genetically altered via myogenin-Cre. Lastly, autophagy flux was significantly less in injured versus uninjured muscles (-26%, P < 0.02) despite the increase in autophagy-related protein content. This suggests autophagy flux is not upregulated to match increases in autophagy machinery after injury and represents a potential bottleneck in the clearance of damaged mitochondria by autophagy.

Project description:BackgroundGut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is strongly involved in the mucosal inflammatory response and immune response. Recent research indicates the involvement of the stimulator of interferons genes (STING) pathway in uncontrolled inflammation and gut mucosal immune response.MethodsWe investigated the role of STING signaling in sepsis and intestinal barrier function using intestinal biopsies from human patients with abdominal sepsis and with an established model of abdominal sepsis in mice.FindingsIn human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls, and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Moreover, elevated STING expression was associated with high levels of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, the intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecal ligation perforation (CLP). STING knockout mice showed an alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice treated with a STING agonist (DMXAA) following CLP developed greater intestinal apoptosis and a more severe systemic inflammatory response. We demonstrated that mitochondrial DNA (mtDNA) was released during sepsis, inducing the intestinal inflammatory response through activating the STING pathway. We finally investigated DNase I administration at 5 hours post CLP surgery, showing that it reduced systemic mtDNA and inflammatory cytokines levels, organ damage, and bacterial translocation, suggesting that inhibition of mtDNA-STING signaling pathway protects against CLP-induced intestinal barrier dysfunction.InterpretationOur results indicate that the STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and through disrupting the intestinal barrier. Our findings suggest that regulation of the mtDNA-STING pathway may be a promising therapeutic strategy to promote mucosal healing and protect the intestinal barrier in septic patients. FUND: National Natural Science Foundation of China.

Project description:BackgroundRecent animal studies have shown that mitochondrial dysfunction initiates and accelerates renal injury in sepsis, but its role in sepsis remains unknown. Mitochondrial stress or dying cells can lead to fragmentation of the mitochondrial genome, which is considered a surrogate marker of mitochondrial dysfunction. Therefore, we evaluated the efficiency of urinary mitochondrial DNA (UmtDNA) as a marker of renal dysfunction during sepsis-induced acute kidney injury (AKI).MethodsWe isolated DNA from plasma and urine of patients. mtDNA levels were quantified by quantitative PCR. Sepsis patients were divided into no AKI, mild AKI, and severe AKI groups according to RIFLE criteria. Additionally, cecal ligation and puncture (CLP) was established in rats to evaluate the association between UmtDNA and mitochondrial function.ResultsA total of 52 (49.5%) developed AKI among enrolled sepsis patients. Increased systemic mtDNA did not correlate with systemic inflammation or acute renal dysfunction in sepsis patients, while AKI did not have an additional effect on circulating mtDNA levels. In contrast, UmtDNA was significantly enriched in severe AKI patients compared with that in the mild AKI or no AKI group, positively correlated with plasma creatinine, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1, and inversely with the estimated glomerular filtration rate. Additionally, UmtDNA increased in rats following CLP-induced sepsis. UmtDNA was predictive of AKI development and correlated with plasma creatinine and blood urea nitrogen in the rat sepsis model. Finally, the UmtDNA level was inversely correlated with the cortical mtDNA copy number and relative expression of mitochondrial gene in the kidney.ConclusionAn elevated UmtDNA level correlates with mitochondrial dysfunction and renal injury in sepsis patients, indicating renal mitochondrial injury induced by sepsis. Therefore, UmtDNA may be regarded as a valuable biomarker for the occurrence of AKI and the development of mitochondria-targeted therapies following sepsis-induced AKI.

Project description:BackgroundMyocardial injury induced by refeeding syndrome (RFS) is one of the important causes of deterioration in critically ill patients. Sirtuin-3 (SIRT3) has been shown to regulate mitochondrial autophagy in myocardial ischemia/reperfusion injury; however, the role of mitochondrial autophagy on RFS-related myocardial injury in patients in critical condition has not been reported on.MethodsThirty Sprague-Dawley (SD) rats were divided into 3 groups (n=10 each group): the control group; the standard calorie refeeding (SCR) group; and the low calorie refeeding (LCR) group. The rats were weighed every third or four days from day 1 to day 14. On day 14, all rats were anesthetized and received an echocardiography test. Blood and bronchoalveolar lavage fluid (BALF) were collected and tested for arterial oxygen pressure (PaO2), phosphorus (P), and calcium (Ca), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin 1 (cTnI), myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6. The histopathological change of hearts and lungs were evaluated, and lung injury score was calculated. Mitochondrial autophagy related proteins (including Beclin1, LC3, mitofusin-2, Mfn2, PINK1, Parkin, and SIRT3) were analyzed using a Western blot. To evaluate the effect of SIRT3, 20 rats were divided into 2 groups (n=10 each group): The adeno-associated virus 9 (AAV9-Nc) group; and the AAV9-SIRT3 overexpression (AAV9-SIRT3) group. The protocols for rats were the same as the SCR group since day 22 after injection of AAV9. The protein expressions of PINK1, Parkin, and SIRT3 were compared between the AAV9-Nc group and AAV9-SIRT3 group.ResultsSCR caused significant decline in cardiac contractility and increased inflammatory cell infiltration in myocardial tissue. Meanwhile, Beclin1, LC3, PINK1, Parkin, and SIRT3 levels decreased, while Mfn2 showed no significant change. Furthermore, significant positive correlations were also found between SIRT3 and P, PINK1, and Parkin, and significant negative correlations were found between SIRT3 and CK-MB, LDH, and cTnI. Overexpression of SIRT3 activated the PINK1/Parkin mediated mitochondrial autophagy.ConclusionsSIRT3 has an essential role in RFS-related myocardial injury during LPS induced chronic sepsis in rats, probably via regulating mitochondrial autophagy.

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Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury.

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Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury.

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