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

Cell reports (Cambridge), 2019-10, Vol.29 (5), p.1261-1273.e6 [Peer Reviewed Journal]

2019 The Authors ;Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. ;ISSN: 2211-1247 ;EISSN: 2211-1247 ;DOI: 10.1016/j.celrep.2019.09.050 ;PMID: 31665638

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Title:
Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury
Author: 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
Subjects: acute kidney injury ; Acute Kidney Injury - chemically induced ; Acute Kidney Injury - metabolism ; Acute Kidney Injury - pathology ; Animals ; bcl-2-Associated X Protein - metabolism ; Cell Line ; Cell Movement - drug effects ; cGAS-STING pathway ; Cisplatin - adverse effects ; cisplatin nephrotoxicity ; Cytosol - metabolism ; DNA, Mitochondrial - metabolism ; Humans ; inflammation ; Inflammation - pathology ; Kidney Tubules - drug effects ; Kidney Tubules - pathology ; Male ; Membrane Proteins - metabolism ; Mice, Inbred C57BL ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - pathology ; mitochondrial DNA ; Neutrophils - drug effects ; Neutrophils - metabolism ; Nucleotidyltransferases - metabolism ; Signal Transduction - drug effects ; tubular cells
Is Part Of: Cell reports (Cambridge), 2019-10, Vol.29 (5), p.1261-1273.e6
Description: Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate immunity. Here, we investigate the role of mitochondrial damage and subsequent activation of the cGAS-STING pathway using a genetically engineered animal model of cisplatin-induced AKI and cultured tubular cells. Cisplatin induced mtDNA leakage into the cytosol—probably through BCL-2-like protein 4 (BAX) pores in the mitochondrial outer membrane—in tubules, with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which is improved in STING-deficient mice. STING knockdown in cultured tubular cells ameliorates inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies support tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we conclude that mitochondrial dysfunction and subsequent activation of the mtDNA-cGAS-STING pathway is a critical regulator of kidney injury. [Display omitted] •cGAS-STING activation and mitochondrial damage in tubules mediate acute kidney injury•cGAS-STING activation induces tubular inflammation and progression of AKI•Mitochondrial DNA leakage into the cytosol increased in AKI-induced tubular damage•Cytosolic mitochondrial DNA activates cGAS-STING signaling in tubular inflammation Acute kidney injury (AKI) is associated with tubular inflammation and mitochondrial dysfunction. Maekawa et al. reveal that tubular mitochondrial damage leads to mtDNA leakage into the cytosol, probably via BAX pores on the mitochondria, activating cGAS-STING signaling and subsequent tubular inflammation in cisplatin-induced AKI. Suppression of the STING ameliorates tubular inflammation and progression of AKI.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 2211-1247
EISSN: 2211-1247
DOI: 10.1016/j.celrep.2019.09.050
PMID: 31665638
Source: Cell Press Free Archives
TestCollectionTL3OpenAccess
GFMER Free Medical Journals
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Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury

2019 The Authors ;Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. ;ISSN: 2211-1247 ;EISSN: 2211-1247 ;DOI: 10.1016/j.celrep.2019.09.050 ;PMID: 31665638

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