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Sepsis-related myocardial injury is associated with Mst1 upregulation, mitochondrial dysfunction and the Drp1/F-actin signaling pathway

  • Xiuling Shang
  • Jun Li
  • Rongguo Yu
  • Pengli Zhu
  • Yingrui Zhang
  • Jingqing Xu
  • Kaihua Chen
  • Min Li
Original Paper
  • 113 Downloads

Abstract

LPS-induced septic cardiomyopathy has been found to be connected with mitochondrial stress through unknown mechanisms. Mitochondrial fission is an early event in mitochondrial dysfunction. The aim of our study was to determine the role and regulatory mechanism of mitochondrial fission in the progression of LPS-induced septic cardiomyopathy, with a particular focus on Mst1 and F-actin. Our data demonstrated that Mst1 expression was rapidly upregulated in LPS-treated hearts and that increased Mst1 promoted cardiomyocyte death by inducing mitochondrial stress. Mechanistically, elevated expression of Mst1 upregulated Drp1, and the latter initiated mitochondrial fission. Excessive mitochondrial fission caused mitochondrial oxidative injury, mitochondrial membrane potential reduction, mitochondrial proapoptotic element translocation into the cytoplasm/nucleus, mitochondrial energy dysfunction and mitochondrial apoptosis activation. Inhibition of mitochondrial fission sustained mitochondrial function and favored cardiomyocyte survival. Furthermore, we identified F-actin degradation as an apparent downstream event of mitochondrial fission activation in the context of LPS-induced septic cardiomyopathy. Stabilization of F-actin attenuated fission-mediated cardiomyocyte death. Altogether, our results define the Mst1/Drp1/mitochondrial fission/F-actin axis as a new signaling pathway that mediates LPS-related septic cardiomyopathy by inducing mitochondrial stress and cardiomyocyte death. Therefore, Mst1 expression, mitochondrial fission modification and F-actin stabilization may serve as potential therapeutic targets for sepsis-related myocardial injury.

Keywords

LPS Septic cardiomyopathy Mst1 F-actin Mitochondrial fission 

Notes

Acknowledgements

The authors are grateful to the Institute of Basic Medicine Science of Qingdao Municipal Hospital.

Author contributions

XS and JL involved in conception and design, performance of experiments, data analysis and interpretation, and manuscript writing; RY and PZ involved in data analysis and interpretation; YZ, JX, KC and ML involved in conception and design, data analysis and interpretation, financial support, and final approval of manuscript.

Funding

This work was supported by Natural Science Foundation of Fujian (Grant number: (2015) 269) and high-level hospital grants from Fujian Provincial Hospital, Fujian province, China (Grant number: (2017) 510#). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have declared that they have no conflicts of interest.

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Xiuling Shang
    • 1
  • Jun Li
    • 1
  • Rongguo Yu
    • 1
  • Pengli Zhu
    • 2
  • Yingrui Zhang
    • 1
  • Jingqing Xu
    • 1
  • Kaihua Chen
    • 1
  • Min Li
    • 1
  1. 1.Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care MedicineFujian Medical UniversityFuzhouChina
  2. 2.Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for GeriatricsFujian Medical UniversityFuzhouChina

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