Acetaldehyde induces phosphorylation of dynamin-related protein 1 and mitochondrial dysfunction via elevating intracellular ROS and Ca
| Autor: | Tingting, Yan, Yan, Zhao |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Dynamins
endocrine system JNK c-Jun-N-terminal kinase Cell Survival MAP Kinase Signaling System Acetaldehyde Drp1 Mitochondrial Dynamics Mfn1 mitofusin 1 PD Parkinson's disease ADH alcohol dehydrogenase Cell Line ROS reactive oxygen species Humans Phosphorylation CaMKII Ca2+/calmodulin-dependent protein kinase II Drp1 dynamin-related protein 1 Neurons ALDH2 aldehyde dehydrogenase 2 NAC N-acetyl-l-cysteine Mitochondria OPA1 optic atrophy 1 Oxidative Stress Protein Transport Ca2+ Calcium AD Alzheimer's disease Reactive Oxygen Species MAPK mitogen-activated protein kinase Research Paper |
| Zdroj: | Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | Excessive alcohol consumption impairs brain function and has been associated with an earlier onset of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Acetaldehyde, the most toxic metabolite of alcohol, has been speculated to mediate the neurotoxicity induced by alcohol abuse. However, the precise mechanisms by which acetaldehyde induces neurotoxicity remain elusive. 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 p38 MAPK while attenuating 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 beneficial for preventing neurotoxicity associated with acetaldehyde and alcohol abuse. |
| Databáze: | OpenAIRE |
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