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Mst1 deletion attenuates renal ischaemia-reperfusion injury: The role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway
- Source :
- Redox Biology, Redox Biology, Vol 20, Iss, Pp 261-274 (2019)
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
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.<br />Graphical abstract fx1<br />Highlights • Mst1 deletion sustains renal function after I/R injury. • Excessive mitochondrial fission accounts for Mst1-mediated mitochondrial apoptosis. • Mst1 enhances reperfusion-mediated mitochondrial fission via Drp1 phosphorylation and F-actin polymerization. • Mst1 regulates Drp1 phosphorylation and F-actin polymerization by activating the GSK3β-p53 axis.
- Subjects :
- 0301 basic medicine
GSK3β-p53 signalling pathway
Clinical Biochemistry
Apoptosis
Mitochondrion
Biochemistry
Mitochondrial Dynamics
Mice
0302 clinical medicine
Renal ischaemia-reperfusion injury
Phosphorylation
lcsh:QH301-705.5
Cytoskeleton
Kidney
lcsh:R5-920
Chemistry
Kinase
Mitochondrial fission
Hepatocyte Growth Factor
Intracellular Signaling Peptides and Proteins
Hedgehog signaling pathway
Cell biology
Mitochondria
medicine.anatomical_structure
Reperfusion Injury
Kidney Diseases
lcsh:Medicine (General)
Research Paper
Signal Transduction
Cell Survival
Drp1
Protein Serine-Threonine Kinases
Cell Line
03 medical and health sciences
F-actin
Proto-Oncogene Proteins
medicine
Animals
Actin
Glycogen Synthase Kinase 3 beta
Organic Chemistry
Actins
030104 developmental biology
lcsh:Biology (General)
Protein Multimerization
Tumor Suppressor Protein p53
Reactive Oxygen Species
030217 neurology & neurosurgery
Gene Deletion
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....39d970b7e260881d2babba27a1c042b5