Yap-Hippo pathway regulates cerebral hypoxia-reoxygenation injury in neuroblastoma N2a cells via inhibiting ROCK1/F-actin/mitochondrial fission pathways

Abstract

Yes-associated protein (Yap), a regulator of cellular apoptosis, has been demonstrated to be involved in cerebral ischemia-reperfusion (IR) injury through poorly defined mechanisms. The present study aimed to explore the role of Yap in regulating cerebral IR injury in vitro, with a focus on mitochondrial fission and ROCK1/F-actin pathways. Our data demonstrated that Yap was actually downregulated in N2a cells after cerebral hypoxia-reoxygenation (HR) injury, and that lower expression of Yap was closely associated with increased cell death. However, the reintroduction of Yap was able to suppress the HR-mediated N2a cells death via blocking the mitochondria-related apoptotic signal. At the molecular levels, Yap overexpression sustained mitochondrial potential, normalized the mitochondrial respiratory function, reduced ROS overproduction, limited HtrA2/Omi release from mitochondria into the nucleus, and suppressed pro-apoptotic proteins activation. Subsequently, functional studies have further illustrated that HR-mediated mitochondrial apoptosis was highly regulated by mitochondrial fission, whereas Yap overexpression was able to attenuate HR-mediated mitochondrial fission and, thus, promote N2a cell survival in the context of HR injury. At last, we demonstrated that Yap handled mitochondrial fission via closing ROCK1/F-actin signaling pathways. Activation of ROCK1/F-actin pathways abrogated the protective role of Yap overexpression on mitochondrial homeostasis and N2a cell survival in the setting of HR injury. Altogether, our data identified Yap as the endogenous defender to relieve HR-mediated nerve damage via antagonizing ROCK1/F-actin/mitochondrial fission pathways.

<p>miR-31 Modulates Liver Cancer HepG2 Cell Apoptosis and Invasion via ROCK1/F-Actin Pathways</p>

“…ROCK1/F-actin is reported to promote mitochondrial dysfunction and apoptosis via activating mitochondrial fission. 20,22 Whether mitochondrial fission is involved in miR-31 induced mitochondrial injury and apoptosis in HepG2 cells needs further research.…”

“…20,21 In cerebral ischemia-reperfusion injury, ROCK1/F-actin is involved in Drp1-related mitochondrial fission and followed cellular apoptosis. 22 However, whether miR-31 affects liver cancer HepG2 cell survival and metastasis through the ROCK1/F-actin pathway remains uncertain. Thus, this study aims to explore mechanisms of miR-31 induced tumor suppression with a focus on mitochondrial injury and the ROCK1/F-actin pathway.…”

The emerging role of Hippo signaling in neurodegeneration

“…Re‐introduction of YAP in cerebral hypoxia–reoxygenation (HR) injury conditions conceals HR‐mediated neuronal apoptosis by blocking mitochondrial‐related apoptotic signaling and by handling mitochondrial. Thus, YAP acts as an endogenous defender to nerve damage occurring through HR injury (Geng, Wei, & Wu, ). These Hippo‐targeted therapeutics clearly suggest the potential of this pathway in recuing neurons from aberrant neurodegeneration induced by stroke‐related condition.…”

“…Re-introduction of YAP in cerebral hypoxia-reoxygenation (HR) injury conditions conceals HR-mediated neuronal apoptosis by blocking mitochondrial-related apoptotic signaling and by handling mitochondrial. Thus, YAP acts as an endogenous defender to nerve damage occurring through HR injury (Geng, Wei, & Wu, 2018 Alves et al (2013)…”

“…But whether targeting Hippo pathway can rescue DRPLA is still an unresolved question. Geng et al (2018) secondary to some other cell cycle influencing primary defects. Hence, more research in delineating this relationship is desired to justify the pathophysiological role of Hippo signaling in neurodegenerative disorders.…”