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Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance

Aims: Ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the potential link among these features remains unclear. In this study, we aimed to investigate the spe...

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Autores principales: Zhao, Meng, Wang, Yizhuo, Li, Ling, Liu, Shuyun, Wang, Chengshi, Yuan, Yujia, Yang, Guang, Chen, Younan, Cheng, Jingqiu, Lu, Yanrong, Liu, Jingping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778599/
https://www.ncbi.nlm.nih.gov/pubmed/33408785
http://dx.doi.org/10.7150/thno.50905
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author Zhao, Meng
Wang, Yizhuo
Li, Ling
Liu, Shuyun
Wang, Chengshi
Yuan, Yujia
Yang, Guang
Chen, Younan
Cheng, Jingqiu
Lu, Yanrong
Liu, Jingping
author_facet Zhao, Meng
Wang, Yizhuo
Li, Ling
Liu, Shuyun
Wang, Chengshi
Yuan, Yujia
Yang, Guang
Chen, Younan
Cheng, Jingqiu
Lu, Yanrong
Liu, Jingping
author_sort Zhao, Meng
collection PubMed
description Aims: Ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the potential link among these features remains unclear. In this study, we aimed to investigate the specific role of mitochondrial ROS (mtROS) in initiating mitochondrial DNA (mtDNA) damage and inflammation during IRI-AKI. Methods: The changes in renal function, mitochondrial function, and inflammation in IRI-AKI mice with or without mtROS inhibition were analyzed in vivo. The impact of mtROS on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, mitochondrial respiration, and cytokine release was analyzed in renal tubular cells in vitro. The effects of TFAM knockdown on mtDNA, mitochondrial function, and cytokine release were also analyzed in vitro. Finally, changes in TFAM and mtDNA nucleoids were measured in kidney samples from IRI-AKI mice and patients. Results: Decreasing mtROS levels attenuated renal dysfunction, mitochondrial damage, and inflammation in IRI-AKI mice. Decreasing mtROS levels also reversed the decrease in TFAM levels and mtDNA copy number that occurs in HK2 cells under oxidative stress. mtROS reduced the abundance of mitochondrial TFAM in HK2 cells by suppressing its transcription and promoting Lon-mediated TFAM degradation. Silencing of TFAM abolished the Mito-Tempo (MT)-induced rescue of mitochondrial function and cytokine release in HK2 cells under oxidative stress. Loss of TFAM and mtDNA damage were found in kidneys from IRI-AKI mice and AKI patients. Conclusion: mtROS can promote renal injury by suppressing TFAM-mediated mtDNA maintenance, resulting in decreased mitochondrial energy metabolism and increased cytokine release. TFAM defects may be a promising target for renal repair after IRI-AKI.
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spelling pubmed-77785992021-01-05 Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance Zhao, Meng Wang, Yizhuo Li, Ling Liu, Shuyun Wang, Chengshi Yuan, Yujia Yang, Guang Chen, Younan Cheng, Jingqiu Lu, Yanrong Liu, Jingping Theranostics Research Paper Aims: Ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the potential link among these features remains unclear. In this study, we aimed to investigate the specific role of mitochondrial ROS (mtROS) in initiating mitochondrial DNA (mtDNA) damage and inflammation during IRI-AKI. Methods: The changes in renal function, mitochondrial function, and inflammation in IRI-AKI mice with or without mtROS inhibition were analyzed in vivo. The impact of mtROS on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, mitochondrial respiration, and cytokine release was analyzed in renal tubular cells in vitro. The effects of TFAM knockdown on mtDNA, mitochondrial function, and cytokine release were also analyzed in vitro. Finally, changes in TFAM and mtDNA nucleoids were measured in kidney samples from IRI-AKI mice and patients. Results: Decreasing mtROS levels attenuated renal dysfunction, mitochondrial damage, and inflammation in IRI-AKI mice. Decreasing mtROS levels also reversed the decrease in TFAM levels and mtDNA copy number that occurs in HK2 cells under oxidative stress. mtROS reduced the abundance of mitochondrial TFAM in HK2 cells by suppressing its transcription and promoting Lon-mediated TFAM degradation. Silencing of TFAM abolished the Mito-Tempo (MT)-induced rescue of mitochondrial function and cytokine release in HK2 cells under oxidative stress. Loss of TFAM and mtDNA damage were found in kidneys from IRI-AKI mice and AKI patients. Conclusion: mtROS can promote renal injury by suppressing TFAM-mediated mtDNA maintenance, resulting in decreased mitochondrial energy metabolism and increased cytokine release. TFAM defects may be a promising target for renal repair after IRI-AKI. Ivyspring International Publisher 2021-01-01 /pmc/articles/PMC7778599/ /pubmed/33408785 http://dx.doi.org/10.7150/thno.50905 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zhao, Meng
Wang, Yizhuo
Li, Ling
Liu, Shuyun
Wang, Chengshi
Yuan, Yujia
Yang, Guang
Chen, Younan
Cheng, Jingqiu
Lu, Yanrong
Liu, Jingping
Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
title Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
title_full Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
title_fullStr Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
title_full_unstemmed Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
title_short Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
title_sort mitochondrial ros promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting tfam-mediated mtdna maintenance
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778599/
https://www.ncbi.nlm.nih.gov/pubmed/33408785
http://dx.doi.org/10.7150/thno.50905
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