期刊
CELL METABOLISM
卷 30, 期 4, 页码 784-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.08.003
关键词
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资金
- NIDDK [R01DK076077, R01 DK087635, DP3 DK108220]
- American Diabetes Association [1-17-PDF-036]
- Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program [W81XWH-16-1-0400]
- NIH [DK111495]
- Diabetes Research Center at the University of Pennsylvania [NIH DK19525]
- Cox Institute for Medical Research
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(flox/flox)). 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.
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