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.
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The authors are grateful to the Institute of Basic Medicine Science of Qingdao Municipal Hospital.
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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.
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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.
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Shang, X., Li, J., Yu, R. et al. Sepsis-related myocardial injury is associated with Mst1 upregulation, mitochondrial dysfunction and the Drp1/F-actin signaling pathway. J Mol Hist 50, 91–103 (2019). https://doi.org/10.1007/s10735-018-09809-5
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DOI: https://doi.org/10.1007/s10735-018-09809-5