FEN1-Generated Oxidized DNA Fragments Escape Mitochondria via mPTP- and VDAC-Dependent Channels to License NLRP3 Inflammasome and STING Activation

Xian, Hongxu; Watari, Kosuke; Sánchez-López, Elsa; Shadel, Gerald S.; Karin, Michael

doi:10.2139/ssrn.4022698

Cited by 3 publications

(1 citation statement)

References 58 publications

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“…However, oxidized mtDNA is so large that it needs to be cut into smaller fragments before it can pass through the conversion hole, and this step is done by an enzyme called FEN1. Once cleaved by FEN1, Ox-mtDNA fragments escape through mPTP and enter the cytoplasm, and then they bind to two key factors: nod-like receptor heat protein domain related protein 3 (NLRP3) and cyclic GMP-AMP synthase (cGAS) [ 147 ]. The combination of Ox-mtDNA with NLRP3 and cGAS can not only induce inflammation, but also induce the transcription of PD-L1 in melanoma cells, which leads to immune escape.…”

Section: Mitochondria and Melanomamentioning

confidence: 99%

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

Du,

Yang,

Liu

et al. 2023

J Transl Med

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Malignant melanoma is one of the most common tumours and has the highest mortality rate of all types of skin cancers worldwide. Traditional and novel therapeutic approaches, including surgery, targeted therapy and immunotherapy, have shown good efficacy in the treatment of melanoma. At present, the mainstay of treatment for melanoma is immunotherapy combined with other treatment strategies. However, immune checkpoint inhibitors, such as PD-1 inhibitors, are not particularly effective in the clinical treatment of patients with melanoma. Changes in mitochondrial function may affect the development of melanoma and the efficacy of PD-1 inhibitors. To elucidate the role of mitochondria in the resistance of melanoma to PD-1 inhibitors, this review comprehensively summarises the role of mitochondria in the occurrence and development of melanoma, targets related to the function of mitochondria in melanoma cells and changes in mitochondrial function in different cells in melanoma resistant to PD-1 inhibitors. This review may help to develop therapeutic strategies for improving the clinical response rate of PD-1 inhibitors and prolonging the survival of patients by activating mitochondrial function in tumour and T cells.

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Section: Mitochondria and Melanomamentioning

confidence: 99%

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

Du,

Yang,

Liu

et al. 2023

J Transl Med

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ER-to-lysosome Ca²⁺refilling followed by K⁺efflux-coupled store-operated Ca²⁺entry in inflammasome activation and metabolic inflammation

Kang

Choi

Kim

et al. 2023

Preprint

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We studied lysosomal Ca2+in inflammasome. LPS+palmitic acid (PA) decreased lysosomal Ca2+([Ca2+]Lys) and increased [Ca2+]ithrough mitochondrial ROS, which was suppressed inTrpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated byTrpm2KO. ER→lysosome Ca2+refilling occurred after lysosomal Ca2+release whose blockade attenuated LPS+PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+efflux whose inhibition reduced ER Ca2+content ([Ca2+]ER) and impaired [Ca2+]Lysrecovery. LPS+PA activated KCa3.1 channel, a Ca2+-activated K+channel. Inhibitors of KCa3.1 channel orKcnn4KO reduced [Ca2+]ER, [Ca2+]iincrease or inflammasome by LPS+PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+release sustained by ER→lysosome Ca2+refilling and K+efflux through KCa3.1 channel in inflammasome and metabolic inflammation.

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Biting the hand that feeds: Metabolic determinants of cell fate during infection

Fraschilla

Evavold

2022

Front. Immunol.

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Metabolic shifts can occur in cells of the innate immune system in response to microbial infection. Whether these metabolic shifts benefit host defense and propagation of an immune response appears to be context dependent. In an arms race, host-adapted microbes and mammalian cells vie for control of biosynthetic machinery, organelles, and metabolites. Herein, we discuss the intersection of host metabolism and cell-intrinsic immunity with implications for cell fate during infection. Sensation of microbial ligands in isolation results in host metabolic shifts that imbues normal innate immune function, such as cytokine secretion. However, living microbes have an arsenal of effectors and strategies to subvert cell-intrinsic immune responses by manipulating host metabolism. Consequently, host metabolism is monitored as an indicator of invasion or manipulation by a pathogen, primarily through the actions of guard proteins and inflammasome pathways. In this review, we frame initiation of cell-intrinsic immunity in the context of host metabolism to include a physiologic “Goldilocks zone” of allowable shifts with guard circuits monitoring wide perturbations away from this zone for the initiation of innate immune responses. Through comparison of studies with purified microbial ligands, dead microbes, and live pathogens we may begin to understand how shifts in metabolism determine the outcome of host-pathogen interactions.

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FEN1-Generated Oxidized DNA Fragments Escape Mitochondria via mPTP- and VDAC-Dependent Channels to License NLRP3 Inflammasome and STING Activation

Cited by 3 publications

References 58 publications

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

ER-to-lysosome Ca²⁺refilling followed by K⁺efflux-coupled store-operated Ca²⁺entry in inflammasome activation and metabolic inflammation

Biting the hand that feeds: Metabolic determinants of cell fate during infection

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FEN1-Generated Oxidized DNA Fragments Escape Mitochondria via mPTP- and VDAC-Dependent Channels to License NLRP3 Inflammasome and STING Activation

Cited by 3 publications

References 58 publications

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

ER-to-lysosome Ca2+refilling followed by K+efflux-coupled store-operated Ca2+entry in inflammasome activation and metabolic inflammation

Biting the hand that feeds: Metabolic determinants of cell fate during infection

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Resources

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ER-to-lysosome Ca²⁺refilling followed by K⁺efflux-coupled store-operated Ca²⁺entry in inflammasome activation and metabolic inflammation