Acetaldehyde induces phosphorylation of dynamin-related protein 1 and mitochondrial dysfunction via elevating intracellular ROS and Ca2+ levels

In this study, it was found that acetaldehyde treatment induced excessive mitochondrial fragmentation, impaired mitochondrial function and caused cytotoxicity in cortical neurons and SH-SY5Y cells. Further analyses showed that acetaldehyde induced the phosphorylation of mitochondrial fission related protein dynamin-related protein 1 (Drp1) at Ser616 and promoted its translocation to mitochondria. The elevation of Drp1 phosphorylation was partly dependent on the reactive oxygen species (ROS)-mediated activation of c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), as N-acetyl-l-cysteine (NAC) pretreatment inhibited the activation of JNK and p38MAPK while attenuated Drp1 phosphorylation in acetaldehyde-treated cells. In addition, acetaldehyde treatment elevated intracellular Ca2+ level and activated Ca2+/calmodulin-dependent protein kinase II (CaMKII). Pretreatment of CaMKII inhibitor prevented Drp1 phosphorylation in acetaldehyde-treated cells and ameliorated acetaldehyde-induced cytotoxicity, suggesting that CaMKII was a key effector mediating acetaldehyde-induced Drp1 phosphorylation and mitochondrial dysfunction. Taken together, acetaldehyde induced cytotoxicity by promoting excessive Drp1 phosphorylation and mitochondrial fragmentation. Both ROS and Ca2+-mediated signaling pathways played important roles in acetaldehyde-induced Drp1 phosphorylation. The results also suggested that prevention of oxidative stress by antioxidants might be beneficia...
Source: Redox Biology - Category: Biology Source Type: research