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

• Main Authors: Hongyan Li, Jianxun Feng, Yunfang Zhang, Junxia Feng, Qi Wang, Shili Zhao, Ping Meng, Jingchun Li
• Format: Article
• Language: English
• Published: Elsevier 2019-01-01
• Series: Redox Biology
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213231718307079

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