ABSTRACT
Changes in calcium signalling are crucial for the development of glioma cells. Whether mitochondrial calcium balance is involved in glial cell development is still unknown. Mitochondrial Calcium Uniporter (MCU) plays an important role in regulating glioma progression. In this work, we found that MCU and p38 expression were positively correlated with glioma grade and the degree tumour progression. MCU increases glioma cell migration by upregulating p38. Furthermore, p38 promotes glioma progression by activating Transcription Factor EB (TFEB)-mediated autophagy. Thus, MCU promotes glioma cell migration by activating autophagy in a p38/TFEB pathway-dependent manner, which provides a theoretical basis for new therapeutic targets for gliomas.
ABSTRACT
Rotenone, a widely used pesticide, causes dopaminergic neurons loss and increase the risk of Parkinson's disease (PD). However, few studies link the role of PARP1 to neuroinflammatory response and autophagy dysfunction in rotenone-induced neurodegeneration. Here, we identified that PARP1 overactivation caused by rotenone led to autophagy dysfunction and NLRP3-mediated inflammation. Further results showed that PARP1 inhibition could reduce NLRP3-mediated inflammation, which was effectively eliminated by TFEB knockdown. Moreover, PARP1 poly(ADP-ribosyl)ated TFEB that reduced autophagy. Of note, PARP1 inhibition could rescue rotenone-induced dopaminergic neurons loss. Overall, our study revealed that PARP1 blocks autophagy through poly (ADP-ribosyl)ating TFEB and inhibited NLRP3 degradation, which suggests that intervention of PARP1-TFEB-NLRP3 signaling can be a new treatment strategy for rotenone-induced neurodegeneration.
Subject(s)
Parkinson Disease , Rotenone , Humans , Rotenone/toxicity , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , Autophagy , Inflammation , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/pharmacology , Poly (ADP-Ribose) Polymerase-1/geneticsABSTRACT
Rotenone, a component of pesticides, is widely used in agriculture and potentially causes Parkinson's disease (PD). However, the regulatory mechanisms of rotenone-induced PD are unclear. Here, we revealed a novel feedback mechanism of p38-Parkin-ROS regulating rotenone-induced PD. Rotenone treatment led to not only the activation of p38 but also Parkin inactivation and reactive oxygen species (ROS) overproduction in SN4741 cells. Meanwhile, p38 activation regulated Parkin phosphorylation at serine 131 to disrupt Parkin-mediated mitophagy. Notably, both p38 inhibition and Parkin overexpression decreased ROS levels. Additionally, the ROS inhibitor N-acetyl-l-cysteine (NAC) inhibited p38 and activated Parkin-mediated mitophagy. Both p38 inhibition and the ROS inhibitor NAC exerted a protective effect by restoring cell death and mitochondrial function in rotenone-induced PD models. Based on these results, the p38-Parkin-ROS signaling pathway is involved in neurodegeneration. This pathway represents a valuable treatment strategy for rotenone-induced PD, and our study provides basic research evidence for the safe use of rotenone in agriculture.
