Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury

Maekawa, Hiroshi; Inoue, Tsuyoshi; Ouchi, Haruki; Jao, Tzu-Ming; Inoue, Reiko; Nishi, Hiroshi; Fujii, Rie; Ishidate, Fumiyoshi; Tanaka, Tetsuhiro; Tanaka, Yosuke; Hirokawa, Nobutaka; Nangaku, Masaomi; Inagi, Reiko

doi:10.1016/j.celrep.2019.09.050

Cited by 320 publications

(220 citation statements)

References 57 publications

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“…It has been shown that deletion of Tfam leads to mtDNA escape into the cytoplasm and activation of the innate immune pathway through cGAS-STING activation which plays key roles in immunity, inflammation, senescence and cancer 44,63,73,74 . In addition to the recent identification of the importance of this signaling pathway in mouse models of acute kidney injury, chronic kidney disease and fibrosis 43,44 , our studies also show increased expression of STING in aging kidneys, and its downregulation following treatment with the pan-ERR agonist.…”

Section: Discussionsupporting

confidence: 67%

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Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Wang

Myakala

Libby

et al. 2019

Preprint

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ABSTRACTBackgroundA gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR).MethodsA pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. In addition, 21-month-old mice were treated with a STING inhibitor for 3 weeks.ResultsRemarkably, only an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression.ConclusionsOur studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.Significance StatementThere is an increasing need for prevention and treatment strategies for age-related kidney disease. The hallmarks of aging kidneys are decreased mitochondrial function and increased inflammation. The expression of the nuclear hormone receptors estrogen-related receptors (ERRs) are decreased in aging human and mouse kidneys. This paper investigates the role of ERRs in the aging kidney. Treatment of aging mice with a pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING signaling pathways. Treatment of aging mice with a STING inhibitor decreased inflammation and increased mitochondrial gene expression. These findings identify ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

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Section: Discussionsupporting

confidence: 67%

“…Recently, several studies have shown that damaged mitochondria may trigger inflammation via cGAS-STING pathway in kidney disease 43,44 . TFAM is a key regulator of mitochondrial gene expression 45 and is crucial for maintaining mtDNA structure, transcription, and replication 46 .…”

Section: Pan-err Agonist Treatment Modulates Mitochondrial Metabolismmentioning

confidence: 99%

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Wang

Myakala

Libby

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…96 It has also been shown that cGAS-STING activation induces tubular inflammation and progression of acute kidney injury. 98 Consistent with these studies, the cGAS-STING pathway has also been linked to lung injury and inflammation. Deficiency in cGAS or STING ameliorates silica-induced lung inflammation, 112 and endothelial cGAS signaling activation promotes inflammatory lung injury.…”

Section: Lung Inflammation and Fibrosissupporting

confidence: 57%

“…97 Mitochondrial dysfunction and subsequent activation of the cGAS-STING signaling is a critical regulator of kidney injury and fibrosis. 98,99 Recently, Huang et al reported mtDNA activates cGAS-mediated cGAMP generation, which suppresses endothelial cell proliferation, thus promoting lung inflammatory injury. 100 Interestingly, in the context of infection, there is an escape of mtDNA into the cytoplasm, where it activates cGAS-mediated type I interferon generation, conferring broad pathogen resistance.…”

Section: Compartmentalizationmentioning

confidence: 99%

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

Serrano

Davis

et al. 2020

FASEB j.

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The presence of DNA in the cytosol is usually a sign of microbial infections, which alerts the host innate immune system to mount a defense response. Cyclic GMP‐AMP synthase (cGAS) is a critical cytosolic DNA sensor that elicits robust innate immune responses through the production of the second messenger, cyclic GMP‐AMP (cGAMP), which binds and activates stimulator of interferon genes (STING). However, cGAS binds to DNA irrespective of DNA sequence, therefore, self‐DNA leaked from the nucleus or mitochondria can also serve as a cGAS ligand to activate this pathway and trigger extensive inflammatory responses. Dysregulation of the cGAS‐STING pathway is responsible for a broad array of inflammatory and autoimmune diseases. Recently, evidence has shown that self‐DNA release and cGAS‐STING pathway over‐activation can drive lung disease, making this pathway a promising therapeutic target for inflammatory lung disease. Here, we review recent advances on the cGAS‐STING pathway governing self‐DNA sensing, highlighting its role in pulmonary disease.

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“…It also leads to death of epithelial cells through the NLRP3 pathway and pulmonary fibrosis (193). Similarly, mtDNA release in renal tubule cells has been found to be associated with acute kidney injury by cytotoxic drugs and chronic renal fibrosis (194,195).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury

Cited by 320 publications

References 57 publications

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

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