DNA-PKcs promotes sepsis-induced multiple organ failure by triggering mitochondrial dysfunction

Rongjun Zou, Jun Tao, Junxiong Qiu, Huimin Lu, Jianhua Wu, Hang Zhu, Ruibing Li, David Mui, Sam Toan, Xing Chang, Hao Zhou, Xiaoping Fan

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Multiple organ failure is the commonest cause of death in septic patients. Objectives: This study was undertaken in an attempt to elucidate the functional importance of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) on mitochondrial dysfunction associated with the development and progression of sepsis-related multiple organ dysfunction syndrome (MODS). Methods: Cardiomyocyte-specific DNA-PKcs knockout (DNA-PKcsCKO) mice, liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice, and kidney tubular cell-specific DNA-PKcs knockout (DNA-PKcsTKO) mice were used to generate an LPS-induced sepsis model. Echocardiography, serum biochemistry, and tissue microscopy were used to analyze organ damage and morphological changes induced by sepsis. Mitochondrial function and dynamics were determined by qPCR, western blotting, ELISA, and mt-Keima and immunofluorescence assays following siRNA-mediated DNA-PKCs knockdown in cardiomyocytes, hepatocytes, and kidney tubular cells. Results: DNA-PKcs deletion attenuated sepsis-mediated myocardial damage through improving mitochondrial metabolism. Loss of DNA-PKcs protected the liver against sepsis through inhibition of mitochondrial oxidative damage and apoptosis. DNA-PKcs deficiency sustained kidney function upon LPS stress through normalization of mitochondrial fission/fusion events, mitophagy, and biogenesis. Conclusion: We conclude that strategies targeting DNA-PKcs expression or activity may be valuable therapeutic options to prevent or reduce mitochondrial dysfunction and organ damage associated with sepsis-induced MODS.

Original languageEnglish (US)
JournalJournal of Advanced Research
DOIs
StateAccepted/In press - 2022

Bibliographical note

Funding Information:
This study was supported by grants from the National Natural Science Foundation of China (No. 81900252 , 82000537 , 82170241 , and 81870249 ). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2022

Keywords

  • DNA-PKcs
  • Heart
  • MODS
  • Mitochondria
  • Sepsis

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