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Theranostics 2021; 11(4):1845-1863. doi:10.7150/thno.50905 This issue Cite

Research Paper

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

Meng Zhao1#, Yizhuo Wang1#, Ling Li2, Shuyun Liu1, Chengshi Wang1, Yujia Yuan1, Guang Yang3, Younan Chen1, Jingqiu Cheng1, Yanrong Lu1, Jingping Liu1✉

1. Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
2. Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China.
3. Animal Center, West China Hospital, Sichuan University, Chengdu, China.
#Co-first authors that contributed equally to this work.

✉ Corresponding author: Jingping Liu, Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, No. 1 Keyuan 4th Road, Gaopeng Ave, Chengdu 610041, China. Tel.: +86-28-85164029; Fax: +86-28-85164030; E-mail: liu More

Citation:
Zhao M, Wang Y, Li L, Liu S, Wang C, Yuan Y, Yang G, Chen Y, Cheng J, Lu Y, Liu J. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics 2021; 11(4):1845-1863. doi:10.7150/thno.50905. https://www.thno.org/v11p1845.htm
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Abstract

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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.

Keywords: acute kidney injury, mitochondria, mtDNA, ROS, TFAM

Citation styles

APA
Zhao, M., Wang, Y., Li, L., Liu, S., Wang, C., Yuan, Y., Yang, G., Chen, Y., Cheng, J., Lu, Y., Liu, J. (2021). Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics, 11(4), 1845-1863. https://doi.org/10.7150/thno.50905.

ACS
Zhao, M.; Wang, Y.; Li, L.; Liu, S.; Wang, C.; Yuan, Y.; Yang, G.; Chen, Y.; Cheng, J.; Lu, Y.; Liu, J. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics 2021, 11 (4), 1845-1863. DOI: 10.7150/thno.50905.

NLM
Zhao M, Wang Y, Li L, Liu S, Wang C, Yuan Y, Yang G, Chen Y, Cheng J, Lu Y, Liu J. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics 2021; 11(4):1845-1863. doi:10.7150/thno.50905. https://www.thno.org/v11p1845.htm

CSE
Zhao M, Wang Y, Li L, Liu S, Wang C, Yuan Y, Yang G, Chen Y, Cheng J, Lu Y, Liu J. 2021. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics. 11(4):1845-1863.

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