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

Abstract

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.

Differential ROS‐Mediated Phosphorylation of Drp1 in Mitochondrial Fragmentation Induced by Distinct Cell Death Conditions in Cerebellar Granule Neurons

“…To further assess the role of mtROS in mitochondrial fission, we evaluated the activation of Drp1 mediated by its phosphorylation at Ser616 in neurons treated with K5 or ST. In the case of K5, we found an increase in Drp1 phosphorylation that correlated with the observed increase in mtROS and mitochondrial fission (Figure 4(a)), in agreement with previous studies [42,71]. Moreover, we observed that MitoTEMPO significantly reduced the increase of p-Drp1 induced by K5 (Figure 4(b)), suggesting that Drp1 phosphorylation could be mediated by the mtROS induced by potassium deprivation.…”

“…A possible explanation for the observed differences in Drp1 phosphorylation by K5 and ST could be the distinct signaling pathways activated by each condition. Drp1dependent mitochondrial fragmentation is regulated by several kinases, including CDK5 [84], CaMKII [82,83], ERK1/2, PKC, JNK, and p38 in different models [71,85,86]. We have previously reported that both models of apoptotic death showed differences in their molecular mechanisms of action.…”

“…The impairment of mitochondrial morphology has been related to increased ROS levels in different experimental models [43,46,50,71], including the use of hydrogen peroxide in neuroblastoma cells and cultured hippocampal neurons [50,70]. Particularly, it has been reported that a reduction in mtROS decreased the mitochondrial fragmentation [50,72].…”

Red Blood Cell Distribution Width as a Predictor of 28‐Day Mortality in Critically Ill Patients With Alcohol Use Disorder

“…Multiple mechanisms may play a role in the relationship between RDW and prognosis in critically ill patients with AUD. First, the alcohol metabolite, acetaldehyde, can increase the generation of free radicals, such as reactive oxygen and nitrogen, causing damage to cells or tissues (Wakabayashi, 2019; Yan and Zhao, 2020). Acetaldehyde affects the normal development of red blood cells, reduces their oxygen‐carrying capacity, and shortens the life of these cells (Waris et al, 2020).…”

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

“…Human neurons treated with ethanol showed an elevated synthesis of RONS linked to the activation of NADPH oxidase (NOX, EC 1.6.3.1), xanthine oxidase (XOX, EC 1.17.3.2), and inducible nitric oxide synthase (iNOS, EC 1.14.13.39) via acetaldehyde [152]. In neuroblastoma SH-SY5Y cells, acetaldehyde provoked mitochondrial fragmentation and cell damage in a ROS formation and calciumdependent manner by phosphorylating Drp1 (dynamin-related protein1), a key regulator of mitochondrial fission [84]. In neurovascular tissues, acetaldehyde induces oxidant production enzymes, NADPH oxidase, and iNOS [153].…”