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Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis.
Citation | “Mitochondrial Damage And Activation Of The Sting Pathway Lead To Renal Inflammation And Fibrosis.”. Cell Metabolism, pp. 784-799.e5. . |
Center | University of Pennsylvania |
Author | Ki Wung Chung, Poonam Dhillon, Shizheng Huang, Xin Sheng, Rojesh Shrestha, Chengxiang Qiu, Brett A Kaufman, Jihwan Park, Liming Pei, Joseph Baur, Matthew Palmer, Katalin Susztak |
Keywords | TFAM, cGAS-STING pathway, Chronic kidney disease, Innate immunity, mitochondrial DNA, mitochondrial transcription factor A, renal fibrosis |
Abstract |
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. |
Year of Publication |
2019
|
Journal |
Cell metabolism
|
Volume |
30
|
Issue |
4
|
Number of Pages |
784-799.e5
|
Date Published |
10/2019
|
ISSN Number |
1932-7420
|
DOI |
10.1016/j.cmet.2019.08.003
|
Alternate Journal |
Cell Metab.
|
PMID |
31474566
|
PMCID |
PMC7054893
|
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