RRC ID 58937
Author Maekawa H, Inoue T, Ouchi H, Jao TM, Inoue R, Nishi H, Fujii R, Ishidate F, Tanaka T, Tanaka Y, Hirokawa N, Nangaku M, Inagi R.
Title Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury.
Journal Cell Rep
Abstract 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.
Volume 29(5)
Pages 1261-1273.e6
Published 2019-10-29
DOI 10.1016/j.celrep.2019.09.050
PII S2211-1247(19)31238-0
PMID 31665638
MeSH Acute Kidney Injury / chemically induced Acute Kidney Injury / metabolism* Acute Kidney Injury / pathology* Animals Cell Line Cell Movement / drug effects Cisplatin / adverse effects Cytosol / metabolism DNA, Mitochondrial / metabolism Humans Inflammation / pathology* Kidney Tubules / drug effects Kidney Tubules / pathology Male Membrane Proteins / metabolism* Mice, Inbred C57BL Mitochondria / drug effects Mitochondria / metabolism Mitochondria / pathology* Neutrophils / drug effects Neutrophils / metabolism Nucleotidyltransferases / metabolism* Signal Transduction / drug effects bcl-2-Associated X Protein / metabolism
IF 8.109
Times Cited 15
Mice RBRC09881