Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

Miao, Naijun; Wang, Zhuning; Wang, Qinlan; Xie, Hongyan; Yang, Ninghao; Wang, Yanzhe; Wang, Jin; Kang, Haixia; Bai, Wenjuan; Wang, Yuanyuan; He, Rui; Yan, Kepeng; Wang, Yan; Hu, Qiongyi; Liu, Zhaoyuan; Li, Fubin; Wang, Rui; Ginhoux, Florent; Zhang, Xiaoling; Yin, Jianyong; Lü, Limin; Wang, Jing

doi:10.1038/s41467-023-36522-z

Cited by 45 publications

(41 citation statements)

References 74 publications

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“…Although NETs are mainly composed of chromosomal DNA, successive work showed mtDNA could be released with NETs in lupus-like disease [19,31], suggesting a direct involvement of mtDNA in NETs formation. Previous study has con rmed that cell-free mtDNA triggers NETs formation by TLR9 pathway during lung transplantation [7] and by cGAS-STING pathway in sickle cell disease [32].…”

Section: Discussionmentioning

confidence: 99%

GSDMD promotes neutrophil extracellular traps via mtDNA-cGAS-STING pathway during lung ischemia/reperfusion.

Lin

Zhao

Liang

et al. 2023

Preprint

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Lung ischemia/reperfusion injury (LIRI) is a complex pathophysiological process, with the histopathological hallmark of neutrophils migratinginto the lungs. Neutrophil extracellular traps (NETs) have been suggested to exert a critical role in the pathogenesis of inflammation and infection in human and animals, while the exact functions and underlying mechanisms of NETs in LIRI remain insufficiently elucidated. In this study, we investigated the role of pore-forming protein gasdermin D (GSDMD) on NETs release in LIRI induced by lung ischemia/reperfusion (I/R). We found that disulfiram, a GSDMD inhibitor, dramatically reduced NETs release and pathological injury in lung I/R in vivoand in vitro. Additionally, GSDMD caused mitochondrial DNA (mtDNA) leaking into the neutrophil cytosol, and then the cytoplasmic mtDNA activated the cGAS-STING signaling pathway and stimulated NETs formation in lung I/R. Furtherly, inhibition of cGAS/STING pathway could inhibit cytosol mtDNA mediated NETs formation.

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Section: Discussionmentioning

confidence: 99%

GSDMD promotes neutrophil extracellular traps via mtDNA-cGAS-STING pathway during lung ischemia/reperfusion.

Lin

Zhao

Liang

et al. 2023

Preprint

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“…4N) and the opening of mitochondrial permeability transition pore (mPTP) (Fig. 5D), allows for easier release of oxidatively damaged mtDNA into the cytoplasm (42)(43)(44). To date, several pathways including BAX/BAK macropore (43), mPTP (42), and N-terminal gasdermin D (GSDMD-N) (45) have been reported to be involved in the release of mtDNA.…”

Section: Midrs Damages Mitochondria To Activate Cytoplasmic Dna Sensorsmentioning

confidence: 99%

Genotype-specific precision tumor therapy using mitochondrial DNA mutation-induced drug release system

Li,

Xu,

et al. 2023

Sci. Adv.

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Precise killing of tumor cells without affecting surrounding normal cells is a challenge. Mitochondrial DNA (mtDNA) mutations, a common genetic variant in cancer, can directly affect metabolic homeostasis, serving as an ideal regulatory switch for precise tumor therapy. Here, we designed a mutation-induced drug release system (MIDRS), using the single-nucleotide variation (SNV) recognition ability and trans-cleavage activity of Cas12a to convert tumor-specific mtDNA mutations into a regulatory switch for intracellular drug release, realizing precise tumor cell killing. Using Ce6 as a model drug, MIDRS enabled organelle-level photodynamic therapy, triggering innate and adaptive immunity simultaneously. In vivo evaluation showed that MIDRS MT could identify tumor tissue carrying SNVs in mtDNA in unilateral, bilateral, and heterogeneous tumor models, producing an excellent antitumor effect (~82.6%) without affecting normal cells and thus resulting in a stronger systemic antitumor immune response. Additionally, MIDRS was suitable for genotype-specific precision drug release of chemotherapeutic drugs. This strategy holds promise for mutation-specific personalized tumor treatment approaches.

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“…Gasdermin D (GSDMD), a pore-forming protein, has been shown to promote NETs formation [10,11]. A recent study demonstrated that oxidation of mtDNA (Ox-mtDNA) promotes GSDMD-N oligomerization and cell death in neutrophils in SLE [12 ▪ ]. Notably, Ox-mtDNA is essential for GSDMD-N oligomerization and subsequent cell death [12 ▪ ].…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

“…A recent study demonstrated that oxidation of mtDNA (Ox-mtDNA) promotes GSDMD-N oligomerization and cell death in neutrophils in SLE [12 ▪ ]. Notably, Ox-mtDNA is essential for GSDMD-N oligomerization and subsequent cell death [12 ▪ ]. Therefore, the interaction between Ox-mtDNA and GSDMD establishes a positive feedback loop, ensuring the release of extracellular DNA and pro-inflammatory programmed cell death (PCD) in neutrophils in SLE.…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

Recent advances on neutrophil dysregulation in the pathogenesis of rheumatic diseases

Chen,

Wang,

Liu

et al. 2023

Current Opinion in Rheumatology

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Purpose of review The exact pathogenic mechanisms of rheumatic diseases (RMD) remain largely unknown. Increasing evidence highlights a pathogenic role of neutrophil dysregulation in the development of RMD. Recent findings The purpose of this review is to present a current overview of recent advancements in understanding the role of neutrophil dysfunction in the development of RMD. Additionally, this review will discuss strategies for targeting pathways associated with neutrophil dysregulation as potential treatments for RMD. One specific aspect of neutrophil dysregulation, known as neutrophil extracellular traps (NETs), will be explored. NETs have been found to contribute to chronic pulmonary inflammation and fibrosis, as well as serve as DNA scaffolds for binding autoantigens, including both citrullinated and carbamylated autoantigens. Putative therapies, such as 6-gingerol or defibrotide, have demonstrated beneficial effects in the treatment of RMD by suppressing NETs formation. Summary Recent advances have significantly reinforced the crucial role of neutrophil dysregulation in the pathogenesis of RMD. A deeper understanding of the potential mechanisms underlying this pathogenic process would aid in the development of more precise and effective targeting strategies, thus ultimately improving the outcomes of RMD.

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Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

Cited by 45 publications

References 74 publications

GSDMD promotes neutrophil extracellular traps via mtDNA-cGAS-STING pathway during lung ischemia/reperfusion.

GSDMD promotes neutrophil extracellular traps via mtDNA-cGAS-STING pathway during lung ischemia/reperfusion.

Genotype-specific precision tumor therapy using mitochondrial DNA mutation-induced drug release system

Recent advances on neutrophil dysregulation in the pathogenesis of rheumatic diseases

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