Circulating cell-free mtDNA release is associated with the activation of cGAS-STING pathway and inflammation in mitochondrial diseases

Zhao, Xutong; Yu, Meng; Zhao, Yawen; Zheng, Yiming; Meng, Lingchao; Du, Kang; Xie, Zhiying; Lv, He; Zhang, Wei; Liu, Jing; Wang, Qingqing; Yuan, Yun; Wang, Zhaoxia; Deng, Jianwen

doi:10.1007/s00415-022-11146-3

Cited by 12 publications

(9 citation statements)

References 43 publications

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“…However, there is limited direct evidence for the occurrence of DNA damage in the brains of human patients with AUD. Under certain physiological or pathological conditions, such as pregnancy, organ transplantation, mitochondrial diseases, and cancers, affected tissues may release cell‐free DNA into the circulatory system throughout the body 38,39 . The quantification of circulating cell‐free DNA levels has also been used to evaluate CNS diseases such as schizophrenia and brain tumors 40–42 .…”

Section: Discussionmentioning

confidence: 99%

“…Under certain physiological or pathological conditions, such as pregnancy, organ transplantation, mitochondrial diseases, and cancers, affected tissues may release cell-free DNA into the circulatory system throughout the body. 38,39 The quantification of circulating cell-free DNA levels has also been used to evaluate CNS diseases such as schizophrenia and brain tumors. [40][41][42] In the context of cancer, there is no connection between circulating cell-free DNA levels and alcohol consumption.…”

Section: Discussionmentioning

confidence: 99%

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Activation of STING signaling aggravates chronic alcohol exposure‐induced cognitive impairment by increasing neuroinflammation and mitochondrial apoptosis

Lin,

Li,

et al. 2024

CNS Neurosci Ther

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AimsChronic alcohol exposure leads to persistent neurological disorders, which are mainly attributed to neuroinflammation and apoptosis. Stimulator of IFN genes (STING) is essential in the cytosolic DNA sensing pathway and is involved in inflammation and cellular death processes. This study was to examine the expression pattern and biological functions of STING signaling in alcohol use disorder (AUD).MethodsCell‐free DNA was extracted from human and mouse plasma. C57BL/6J mice were given alcohol by gavage for 28 days, and behavior tests were used to determine their mood and cognition. Cultured cells were treated with ethanol for 24 hours. The STING agonist DMXAA, STING inhibitor C‐176, and STING‐siRNA were used to intervene the STING. qPCR, western blot, and immunofluorescence staining were used to assess STING signaling, inflammation, and apoptosis.ResultsCirculating cell‐free mitochondrial DNA (mtDNA) was increased in individuals with AUD and mice chronically exposed to alcohol. Upregulation of STING signaling under alcohol exposure led to inflammatory responses in BV2 cells and mitochondrial apoptosis in PC12 cells. DMXAA exacerbated alcohol‐induced cognitive impairment and increased the activation of microglia, neuroinflammation, and apoptosis in the medial prefrontal cortex (mPFC), while C‐176 exerted neuroprotection.ConclusionActivation of STING signaling played an essential role in alcohol‐induced inflammation and mitochondrial apoptosis in the mPFC. This study identifies STING as a promising therapeutic target for AUD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of STING signaling aggravates chronic alcohol exposure‐induced cognitive impairment by increasing neuroinflammation and mitochondrial apoptosis

Lin,

Li,

et al. 2024

CNS Neurosci Ther

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“…To extract ccf‐mtDNA and ccf‐nDNA, a Serum‐Free DNA Extraction Kit with magnetic beads (Tiangen, DP709) was employed. Quantitative real‐time polymerase chain reaction (RT‐qPCR) was conducted following the methodology described in our prior study 15 to measure the levels of ccf‐mtDNA using the mitochondrial NADH dehydrogenase 1 ( MT‐ND1 ) gene and ccf‐nDNA using the beta‐actin ( ACTB ) gene. The reaction mixture, consisting of 20 μL, included 2 μL of circulating cell‐free DNA from serum samples, 1× UltraSYBR Mixture (CW2601), 0.2 μM MT‐ND1 primers or ACTB primers, and nuclease‐free water.…”

Section: Methodsmentioning

confidence: 99%

“…10,11 Circulating cell-free DNA primarily originates from deceased cells of the hematopoietic lineage, with minimal contributions from other tissues. 12,13 Mitochondria-derived ccf-DNA (ccf-mtDNA) serves as an indicator of mitochondrial dysfunction, [14][15][16] and increased levels of nuclear-derived ccf-DNA (ccf-nDNA) have been observed in various disease states, often serving as a marker for disease activity monitoring. [17][18][19] Elevated ccf-DNA levels have been detected in the sera/ plasma of patients with several conditions, including cancer and autoimmune diseases, notably IIMs.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

Wang,

Zhao,

et al. 2023

Ann Clin Transl Neurol

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ObjectiveAnti‐mitochondrial antibodies (AMAs) are associated with idiopathic inflammatory myopathies (IIMs). We aimed to summarize the clinicopathological characteristics, assess circulating cell‐free mitochondrial DNA (ccf‐mtDNA), and circulating cell‐free nuclear DNA (ccf‐nDNA) in AMA‐associated IIMs.MethodsMedical records of 37 IIMs patients with AMAs were reviewed. Circulating cell‐free mtDNA and ccf‐nDNA levels in sera from IIMs patients with AMAs (n = 21), disease controls (n = 66) and healthy controls (HCs) (n = 23) were measured and compared. Twenty‐eight immune‐mediated necrotizing myopathy (IMNM) patients, 23 dermatomyositis (DM) patients, and 15 anti‐synthetase syndrome (ASS) patients were enrolled as disease controls. Correlations between variables were analyzed.ResultsLimb weakness was observed in 75.7% and neck weakness in 56.8% of patients. Cardiac involvement occurred in 51.4% of patients. Muscle pathology revealed 81.1% of IMNM, 5.4% polymyositis, and 13.5% nonspecific myositis. Microinfarction was observed in 8.1% of patients. Serum ccf‐mtDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p < 0.001), but no significant differences between AMA‐associated IIMs and IMNM, DM, or ASS. Serum ccf‐nDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p = 0.02), and significantly lower than those in DM (p = 0.02). Serum ccf‐nDNA levels correlated negatively with MMT8 total scores (rs = −0.458, p = 0.037) and positively with mRS scores (rs = 0.486, p = 0.025). Serum ccf‐nDNA levels were significantly higher in the non‐remission group (p < 0.01).InterpretationAMA‐associated IIMs exhibit distinct clinicopathological features. Serum ccf‐nDNA may serve as a potential marker for disease severity and prognosis in AMA‐associated IIMs.

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“…Next, the false discovery rate (the Benjamini–Hochberg method) was used to calculate the adjusted P -value. Differentially expressed cytokines/chemokines were defined as those with adjusted P -value < 0.05 and FC >1.2 or <0.83 (absolute logFC > 0.263) ( 18 – 20 ). Heat maps were drawn to screen for and depict the logical connections between differentially expressed cytokines/chemokines.…”

Section: Methodsmentioning

confidence: 99%

Comparison of cytokine/chemokine profiles between dermatomyositis and anti-synthetase syndrome

et al. 2022

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ObjectivesDermatomyositis (DM) and anti-synthetase syndrome (ASS) are autoimmune diseases with multisystem involvement. Despite sharing some clinical and myopathological features, these are two diseases with different pathogeneses and prognoses. We aimed to clarify and compare cytokine/chemokine profiles in both disorders, which may help in the differential diagnosis.Materials and methodsWe collected clinical data and serum samples of consecutive patients with DM and ASS. Quantibody® Human Inflammation Array 3 for cytokines/chemokines was performed in the serum of all participants. Receiver operating characteristic analysis with the area under the curve and Youden's index were performed.ResultsEight newly diagnosed and treatment-naïve patients with DM, nine newly diagnosed and treatment-naïve patients with ASS, and 14 healthy controls were enrolled. Serum C-C motif chemokine ligand (CCL) 2, CCL4, C-X-C motif chemokine ligand (CXCL) 13, and tumor necrosis factor receptor 2 (TNFR2) were increased in patients with both DM and ASS. Serum interleukin (IL)-1 receptor type 1 (IL-1ra), IL-1b, CCL1, CXCL11, and CCL3 were modulated in patients with DM only, and IL-8, CXCL9, and tissue inhibitors of metalloproteinases-1 (TIMP-1) in patients with ASS only. Serum CCL2, CXCL13, and TNFR2 accurately distinguished patients with DM and ASS from healthy controls, as shown by the area under the curve >0.80. Moreover, receiver operating characteristic analysis showed that, as biomarkers for discrimination between DM and ASS, the combination of IL-1ra and TIMP-1, had an area under the curve of 0.944, a sensitivity of 87.5%, and a specificity of 88.9%.ConclusionOur study demonstrated that serum levels of cytokines/chemokines showed a different pattern in newly diagnosed patients with DM and ASS, in which serum IL-1ra and TIMP-1 could be used to distinguish between the two diseases.

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Circulating cell-free mtDNA release is associated with the activation of cGAS-STING pathway and inflammation in mitochondrial diseases

Cited by 12 publications

References 43 publications

Activation of STING signaling aggravates chronic alcohol exposure‐induced cognitive impairment by increasing neuroinflammation and mitochondrial apoptosis

Activation of STING signaling aggravates chronic alcohol exposure‐induced cognitive impairment by increasing neuroinflammation and mitochondrial apoptosis

Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

Comparison of cytokine/chemokine profiles between dermatomyositis and anti-synthetase syndrome

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