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Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis

Cell metabolism, 2019-10, Vol.30 (4), p.784-799.e5 [Peer Reviewed Journal]

Copyright © 2019 Elsevier Inc. All rights reserved. ;ISSN: 1550-4131 ;EISSN: 1932-7420 ;DOI: 10.1016/j.cmet.2019.08.003 ;PMID: 31474566

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Title:
Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis
Author: Chung, Ki Wung ; Dhillon, Poonam ; Huang, Shizheng ; Sheng, Xin ; Shrestha, Rojesh ; Qiu, Chengxiang ; Kaufman, Brett A ; Park, Jihwan ; Pei, Liming ; Baur, Joseph ; Palmer, Matthew ; Susztak, Katalin
Subjects: Animals ; DNA, Mitochondrial - metabolism ; DNA-Binding Proteins - metabolism ; Epithelial Cells - metabolism ; Epithelial Cells - pathology ; Fibrosis ; Humans ; Inflammation - pathology ; Kidney Tubules - metabolism ; Kidney Tubules - pathology ; Male ; Membrane Proteins - metabolism ; Mice ; Mitochondria - metabolism ; Mitochondrial Proteins - metabolism ; RAW 264.7 Cells ; Renal Insufficiency, Chronic - pathology ; Transcription Factors - metabolism
Is Part Of: Cell metabolism, 2019-10, Vol.30 (4), p.784-799.e5
Description: Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the kidneys of patients and animal models with fibrosis, we observed a significant mitochondrial defect, including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfam ). While these mice developed severe mitochondrial loss and energetic deficit by 6 weeks of age, kidney fibrosis, immune cell infiltration, and progressive azotemia causing death were only observed around 12 weeks of age. In renal cells of TFAM KO (knockout) mice, aberrant packaging of the mitochondrial DNA (mtDNA) resulted in its cytosolic translocation, activation of the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Ablation of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating how TFAM sequesters mtDNA to limit the inflammation leading to fibrosis.
Publisher: United States
Language: English
Identifier: ISSN: 1550-4131
EISSN: 1932-7420
DOI: 10.1016/j.cmet.2019.08.003
PMID: 31474566
Source: Cell Press Free Archives
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Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis

Copyright © 2019 Elsevier Inc. All rights reserved. ;ISSN: 1550-4131 ;EISSN: 1932-7420 ;DOI: 10.1016/j.cmet.2019.08.003 ;PMID: 31474566

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