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

Liu, Qinjie; Wu, Jie; Zhang, Xufei; Li, Xuanheng; Wu, Xiuwen; Zhao, Yun; Ren, Jianan

doi:10.1038/s41419-021-03961-9

Cited by 78 publications

(51 citation statements)

References 38 publications

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“…Strikingly, the induction of inflammation and autophagy seems to be cross-talking via STING, as activation of STING interfered with lysosomal acidification, hence disturbing autophagy in mtDNA mediated sepsis-induced acute lung injury. As a consequence, the induction of autophagy or STING deficiency alleviated lung injury (Liu et al, 2021). The proper functioning of the mitophagy also seems to be of great importance for the preservation of renal function.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Chowdhury

Witte

Aich

2022

Front. Cell Dev. Biol.

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Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Chowdhury

Witte

Aich

2022

Front. Cell Dev. Biol.

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“…Hu et al ( 58 ) showed that inhibition of mtDNA release attenuated sepsis-induced inflammatory responses and intestinal injury; therefore, it was hypothesized that inhibition of the mtDNA/cGAS/STING signaling pathway could protect against sepsis-induced organ damage and intestinal barrier dysfunction. Liu et al ( 61 ) revealed that levels of cyclic mtDNA and STING activation were enhanced in patients with severe ALI. In addition, STING activation may serve a key role in mtDNA-mediated lung injury, which promotes inflammatory storm and is involved in autophagy via decreasing lysosomal acidification in an IFN-dependent manner ( 61 ).…”

Section: Effect Of Mtdna On the Occurrence And Development Of Sirsmentioning

confidence: 99%

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

Kong

Song

2022

Mol Med Rep

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Mitochondria are key organelles of cellular energy metabolism; both mitochondrial function and metabolism determine the physiological function of cells and serve an essential role in immune responses. Key damage-associated molecular patterns (daMPs), such as mitochondrial dna and n-formyl peptides, released following severe trauma-induced mitochondrial damage may affect the respiratory chain, enhance oxidative stress and activate systemic inflammatory responses via a variety of inflammation-associated signaling pathways. Severe trauma can lead to sepsis, multiple organ dysfunction syndrome and death. The present review aimed to summarize the pathophysiological mechanisms underlying the effects of human mitochondrial injury-released daMPs on triggering systemic inflammatory responses and to determine their potential future clinical applications in preventing and treating sepsis. Contents1. introduction 2. Structure and function of mitochondria 3. mtdaMPs 4. mtdna 5. effect of mtdna on the occurrence and development of SirS 6. nFPs 7. TFaM 8. mtdaMPs and intestinal barrier dysfunction 9. conclusion can

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“…STING is a universal receptor for cyclic dinucleotides, including the bacterial second messengers 3′-5′-cyclic-di-adenosine-monophosphate (CDA), 3′-5′-cyclic-di-guanosine-monophosphate (CDG), and the newly discovered metazoan second messenger ring GMP–AMP [ 108 ]. The STING pathway is activated by mtDNA and operates in the liver as well as in other tissues, such as in the lungs (in sepsis-induced acute lung injury) and kidneys (in acute kidney injury) [ 109 , 110 ]. In the NASH mouse model, the lack of STING alleviates hepatic steatosis, fibrosis, and nuclear factor (NF)-κB-dependent inflammation even in the presence of mtDNA-induced stimulation of KCs.…”

Section: The Mechanism Of Oxidative Stress Of Kupffer Cells In Nashmentioning

confidence: 99%

Oxidative Stress Is a Key Modulator in the Development of Nonalcoholic Fatty Liver Disease

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and scientific studies consistently report that NAFLD development can be accelerated by oxidative stress. Oxidative stress can induce the progression of NAFLD to NASH by stimulating Kupffer cells, hepatic stellate cells, and hepatocytes. Therefore, studies are underway to identify the role of antioxidants in the treatment of NAFLD. In this review, we have summarized the origins of reactive oxygen species (ROS) in cells, the relationship between ROS and NAFLD, and have discussed the use of antioxidants as therapeutic agents for NAFLD.

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

Cited by 78 publications

References 38 publications

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

Oxidative Stress Is a Key Modulator in the Development of Nonalcoholic Fatty Liver Disease

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