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| Status |
Public on Aug 29, 2019 |
| Title |
Mitochondrial damage activates the STING pathway to promote chronic kidney disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Fibrosis of the kidney is the final common pathway leading to end stage renal failure. By analyzing 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 flox/flox). While these mice developed severe mitochondrial loss and energetic deficit (ATP level decline) by 6 weeks of age, kidney fibrosis, immune cell infiltration and progressive azotemia causing death was only observed around 12 weeks of age. Mechanistic studies demonstrated that in the TFAM KO mice aberrant packaging of the mitochondrial DNA (mtDNA) resulted in escape of the mtDNA into the cytosol of the renal cells, activation of the cytosolic cGAS-STING (Stimulator of interferon genes) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Genetic deletion or pharmacological inhibition of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating that in addition to its essential role in metabolism TFAM sequesters mtDNA to prevent the activation of innate immune pathways and fibrosis.
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| Overall design |
RNA-seq of kidneys of 12 weeks old control mice (Tfam flox/flox without Ksp cre) and Kspcre Tfam flox/flox mice
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| |
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| Contributor(s) |
Ki Wung C, Poonam D, Xin S, Katalin S |
| Citation missing |
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| |
| Submission date |
Jul 26, 2019 |
| Last update date |
Aug 29, 2019 |
| Contact name |
Xin Sheng |
| E-mail(s) |
xin.sheng@pennmedicine.upenn.edu
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| Organization name |
University of Pennsylvania
|
| Lab |
Susztak lab
|
| Street address |
3400 CCB
|
| City |
Philadelphia |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA556870 |
| SRA |
SRP216519 |
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