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

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.

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

“…Mammalian STE20-like kinase 1 (MST1) is a regulator of mitochondrial fission via DRP1 phosphorylation at Ser-616 and enhancement of the F-actin assembly that induces mitochondrial injury, cytochrome c release, and mROS production, thereby promoting tubular cell apoptosis in IRI, which was attenuated by genetic deletion of Mst1 [38]. In human ischemic kidneys with IRI from cadaveric kidney transplants, the duration-dependent increase in tubular apoptosis is directly related to the release of cytochrome c from the mitochondria [39].…”

“…This, in turn, induces superoxide generation by negatively affecting mitochondrial metabolism, the efficiency of the ETC, and ATP production [47]. Cisplatin-induced nephrotoxicity is also associated with increased DRP1-mediated mitochondrial fragmentation, cytochrome c release, apoptosis of proximal tubular cells, and renal injury [38]. Furthermore, blockade of mitochondrial fission abrogated cisplatin-induced proximal tubular cell apoptosis and renal injury and improved kidney function, further attesting to the critical role of mitochondrial dynamics in AKI [35].…”

Elevated intracranial pressure induces IL‑1β and IL‑18 overproduction via activation of the NLRP3 inflammasome in microglia of ischemic adult rats

“…Secondly, the present study did not determine the upstream mechanism by which elevated IcP promotes ROS overproduction in ischemic stroke. It has been found that ischemia damages mitochondria and induces ROS production (36,37). Mitophagy can eliminate damaged mitochondria, reduce ROS production and then alleviate NLRP3 inflammasome activation (38).…”

Imbalance in mitochondrial dynamics induced by low PGC-1α expression contributes to hepatocyte EMT and liver fibrosis

“…Dnm1/Drp1 assemble on the surface of mitochondria and drive membrane constriction and the scission of the inner and outer mitochondrial membranes in a GTP-dependent manner. The endoplasmic reticulum (ER), ER-bound inverted-formin 2 (INF2), and actin assembly at mitochondria-ER contact sites are required for mitochondrial fission [15][16][17] . An increase in phospho-Drp1 levels was detected in mitochondrial outermembrane and forms a large ring-like complex to exert fission activity in sporadic Parkinson's disease cellular models, implicating increased mitochondrial fission in the pathophysiology of Parkinson's diseases 18,19 .…”