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Acetaldehyde Induces Cytotoxicity via Triggering Mitochondrial Dysfunction and Overactive Mitophagy

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Abstract

Overconsumption of alcohol damages brain tissue and causes cognitive dysfunction. It has been suggested that the neurotoxicity caused by excessive alcohol consumption is largely mediated by acetaldehyde, the most toxic metabolite of ethanol. Evidence shows that acetaldehyde impairs mitochondrial function and induces cytotoxicity of neuronal cells; however, the exact mechanisms are not fully understood. The aim of this study was to investigate the role of mitophagy in acetaldehyde-induced cytotoxicity. It was found that acetaldehyde treatment induced mitophagic responses and caused cytotoxicity in SH-SY5Y cells. The levels of light chain 3 (LC3)-II, Beclin1, autophagy-related protein (Atg) 5 and Atg16L1, PTEN-induced putative kinase (PINK)1, and Parkin were significantly elevated, while the level of p62 was reduced in acetaldehyde-treated cells. Acetaldehyde also promoted the accumulation of PINK1 and Parkin on mitochondria and caused a remarkable decrease of mitochondrial mass. Treatment with autophagy inhibitors prevented the decline of mitochondrial mass and alleviated the cytotoxicity induced by acetaldehyde, suggesting that overactive mitophagy might be an important mechanism contributing to acetaldehyde-induced cytotoxicity. Antioxidant N-acetyl-L-cysteine significantly attenuated the mitophagic responses and alleviated the cytotoxicity induced by acetaldehyde, indicating that oxidative stress was a major mediator of the excessive mitophagy induced by acetaldehyde. Taken together, these findings provided new insights into the role of mitophagy and oxidative stress in acetaldehyde-induced cytotoxicity.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China [31371082], Natural Science Foundation of Shandong province (ZR2019MH048), Weihai Science and Technology Development Program, and research fund from Harbin Institute of Technology at Weihai [HIT(WH)Y200902].

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  1. Department of Bioengineering, Harbin Institute of Technology, Weihai, 264209, Shandong, China

    Tingting Yan, Yan Zhao, Zhongyu Jiang & Jiyang Chen

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  1. Tingting Yan
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  2. Yan Zhao
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  3. Zhongyu Jiang
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  4. Jiyang Chen
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TTY contributed to part of the experiments, article writing, and data analyses; YZ supervised the experiments, revised the manuscript, and helped with the technical problems; ZYJ and JYC performed part of the experiments. All authors read and approved the final manuscript.

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Correspondence to Yan Zhao.

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Yan, T., Zhao, Y., Jiang, Z. et al. Acetaldehyde Induces Cytotoxicity via Triggering Mitochondrial Dysfunction and Overactive Mitophagy. Mol Neurobiol 59, 3933–3946 (2022). https://doi.org/10.1007/s12035-022-02828-0

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