The Role of Plasma Cell-Free Mitochondrial DNA and Nuclear DNA in Systemic Lupus Erythematosus

Lee, Hui-Ting; Lin, Cheng‐Chieh; Pan, Siao-Cian; Chen, Weisheng; Tsai, Chang‐Youh; Wei, Yau‐Huei

doi:10.31083/j.fbl2712333

Cited by 3 publications

(4 citation statements)

References 63 publications

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“…Ccf-nDNA is primarily released into the bloodstream from various cellular processes, including NETosis, apoptosis, and necrosis. 13,46,47 Previous studies have reported elevated levels of cell-free DNA and abnormal formation of neutrophil extracellular traps in patients with DM/PM. 22,23 Therefore, we propose that aberrant formation of neutrophil extracellular traps may also contribute to the pathogenesis of AMAassociated IIMs.…”

Section: Discussionmentioning

confidence: 99%

“…We guess that mitochondrial dysfunction partially contributes to the pathogenesis of AMA‐associated IIMs, although mitochondrial damage exists but not unique in AMA‐associated IIMs. Ccf‐nDNA is primarily released into the bloodstream from various cellular processes, including NETosis, apoptosis, and necrosis 13,46,47 . Previous studies have reported elevated levels of cell‐free DNA and abnormal formation of neutrophil extracellular traps in patients with DM/PM 22,23 .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…To explain this difference between mtDNA and nuclear DNA, the authors suggest that SLE patients were undergoing more vital NETosis than lytic NETosis, the former releasing a higher amount of nuclear DNA than mtDNA into the circulation. Furthermore, it is important to note that during NETosis, mitochondrial DNA becomes entrapped in the NET and is not freely found in the plasma [ 62 ]. The observation of lower CFmtDNA in LN is interesting, considering the pivotal role NETosis plays in this pathology [ 63 , 64 , 65 ].…”

Section: Mitochondrial Dysfunction In Lupus Nephritismentioning

confidence: 99%

Mitochondrial Dysfunction in Systemic Lupus Erythematosus with a Focus on Lupus Nephritis

Halfon,

Tankeu,

Ribi

2024

IJMS

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Systemic lupus erythematosus (SLE) is an autoimmune disease affecting mostly women of child-bearing age. Immune dysfunction in SLE results from disrupted apoptosis which lead to an unregulated interferon (IFN) stimulation and the production of autoantibodies, leading to immune complex formation, complement activation, and organ damage. Lupus nephritis (LN) is a common and severe complication of SLE, impacting approximately 30% to 40% of SLE patients. Recent studies have demonstrated an alteration in mitochondrial homeostasis in SLE patients. Mitochondrial dysfunction contributes significantly to SLE pathogenesis by enhancing type 1 IFN production through various pathways involving neutrophils, platelets, and T cells. Defective mitophagy, the process of clearing damaged mitochondria, exacerbates this cycle, leading to increased immune dysregulation. In this review, we aim to detail the physiopathological link between mitochondrial dysfunction and disease activity in SLE. Additionally, we will explore the potential role of mitochondria as biomarkers and therapeutic targets in SLE, with a specific focus on LN. In LN, mitochondrial abnormalities are observed in renal cells, correlating with disease progression and renal fibrosis. Studies exploring cell-free mitochondrial DNA as a biomarker in SLE and LN have shown promising but preliminary results, necessitating further validation and standardization. Therapeutically targeting mitochondrial dysfunction in SLE, using drugs like metformin or mTOR inhibitors, shows potential in modulating immune responses and improving clinical outcomes. The interplay between mitochondria, immune dysregulation, and renal involvement in SLE and LN underscores the need for comprehensive research and innovative therapeutic strategies. Understanding mitochondrial dynamics and their impact on immune responses offers promising avenues for developing personalized treatments and non-invasive biomarkers, ultimately improving outcomes for LN patients.

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“…It is worth noting that there are also dysfunctional mitochondria in SLE. A study reported that a decrease in the mtDNA copy number of plasma leukocytes in SLE patients is related to an increase in the disease activity index and an increase in the plasma DNA oxidative damage marker 8-hydroxy deoxyguanosine level ( 54 ).…”

Section: Self-dna and Cgas-sting Signalingmentioning

confidence: 99%

Updated roles of cGAS-STING signaling in autoimmune diseases

Liu,

2023

Front. Immunol.

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Natural immunity, the first line for the body to defense against the invasion of pathogen, serves as the body’s perception of the presence of pathogens depends on nucleic acid recognition mechanisms. The cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) signaling pathway is considered an essential pattern recognition and effector pathway in the natural immune system and is mainly responsible for recognizing DNA molecules present in the cytoplasm and activating downstream signaling pathways to generate type I interferons and some other inflammatory factors. STING, a crucial junction protein in the innate immune system, exerts an essential role in host resistance to external pathogen invasion. Also, STING, with the same character of inflammatory molecules, is inseparable from the body’s inflammatory response. In particular, when the expression of STING is upregulated or its related signaling pathways are overactivated, the body may develop serious infectious disorders due to the generation of excessive inflammatory responses, non-infectious diseases, and autoimmune diseases. In recent years, accumulating studies indicated that the abnormal activation of the natural immune cGAS-STING signaling pathway modulated by the nucleic acid receptor cGAS closely associated with the development and occurrence of autoimmune diseases (AID). Thereof, to explore an in-depth role of STING and its related signaling pathways in the diseases associated with inflammation may be helpful to provide new avenues for the treatment of these diseases in the clinic. This article reviews the activation process of the cGAS-STING signaling pathways and its related important roles, and therapeutic drugs in AID, aiming to improve our understanding of AID and achieve better diagnosis and treatment of AID.

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The Role of Plasma Cell-Free Mitochondrial DNA and Nuclear DNA in Systemic Lupus Erythematosus

Cited by 3 publications

References 63 publications

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

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

Mitochondrial Dysfunction in Systemic Lupus Erythematosus with a Focus on Lupus Nephritis

Updated roles of cGAS-STING signaling in autoimmune diseases

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