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Redox Biol. 2019 Jan;20:261-274. doi: 10.1016/j.redox.2018.10.012. Epub 2018 Oct 19.

Mst1 deletion attenuates renal ischaemia-reperfusion injury: The role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway.

Author information

1
Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou 510800, China. Electronic address: lihy0726@126.com.
2
Department of Nephorology, Xuhui DIstrict Centeral Hospital of Shanghai, Shanghai 20031, China.
3
Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou 510800, China.

Abstract

Despite extensive research that has been carried out over the past three decades in the field of renal ischaemia-reperfusion (I/R) injury, the pathogenic role of mitochondrial fission in renal I/R injury is poorly understood. The aim of our study is to investigate the molecular mechanism by which mammalian STE20-like kinase 1 (Mst1) participates in renal I/R injury through modifying mitochondrial fission, microtubule cytoskeleton dynamics, and the GSK3β-p53 signalling pathway. Our data demonstrated that genetic ablation of Mst1 improved renal function, alleviated reperfusion-mediated tubular epithelial cell apoptosis, and attenuated the vulnerability of kidney to I/R injury. At the molecular level, Mst1 upregulation exacerbated mitochondrial damage, as evidenced by reduced mitochondrial potential, increased ROS generation, more cyt-c liberation from mitochondria into the cytoplasm, and an activated mitochondrial apoptotic pathway. Furthermore, we demonstrated that I/R-mediated mitochondrial damage resulted from mitochondrial fission, and the blockade of mitochondrial fission preserved mitochondrial homeostasis in the I/R setting. Functional studies have discovered that Mst1 regulated mitochondrial fission through two mechanisms: induction of Drp1 phosphorylation and enhancement of F-actin assembly. Activated Mst1 promoted Drp1 phosphorylation at Ser616, contributing to Drp1 translocation from the cytoplasm to the surface of the mitochondria. Additionally, Mst1 facilitated F-actin polymerization, contributing to mitochondrial contraction. Finally, we confirmed that Mst1 regulated Drp1 post-transcriptional modification and F-actin stabilization via the GSK3β-p53 signalling pathway. Inhibition of GSK3β-p53 signalling provided a survival advantage for the tubular epithelial cell in the context of renal I/R injury by repressing mitochondrial fission. Collectively, our study identified Mst1 as the primary pathogenesis for the development and progression of renal I/R injury via activation of fatal mitochondrial fission by modulating Drp1 phosphorylation, microtubule cytoskeleton dynamics, and the GSK3β-p53 signalling pathway.

KEYWORDS:

Drp1; F-actin; GSK3β-p53 signalling pathway; Mitochondrial fission; Renal ischaemia-reperfusion injury

PMID:
30384260
PMCID:
PMC6205415
DOI:
10.1016/j.redox.2018.10.012
[Indexed for MEDLINE]
Free PMC Article

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