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Cdk5 Promotes Mitochondrial Fission via Drp1 Phosphorylation at S616 in Chronic Ethanol Exposure–Induced Cognitive Impairment

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Abstract

Excessive alcohol consumption can lead to alterations in brain structure and function, even causing irreversible learning and memory disorders. The hippocampus is one of the most sensitive areas to alcohol neurotoxicity in the brain. Accumulating evidence indicates that mitochondrial dysfunction contributes to alcohol neurotoxicity. However, little is known about the underlying molecular mechanisms. In this study, we found that chronic exposure to ethanol caused abnormal mitochondrial fission/fusion and morphology by activating the mitochondrial fission protein dynamin-related protein 1 (Drp1) and upregulating Drp1 receptors, such as fission protein 1 (Fis1), mitochondrial dynamics protein of 49 kDa (Mid49), and mitochondrial fission factor (Mff), combined with decreasing optic atrophy 1 (Opa1) and mitochondrial fusion protein mitofusin 1 (Mfn1) levels. In addition, mitochondrial division inhibitor 1 (mdivi-1) abrogated ethanol-induced mitochondrial dysfunction and improved hippocampal synapses and cognitive function in ethanol-exposed mice. Chronic ethanol exposure also resulted in cyclin-dependent kinase 5 (Cdk5) overactivation, as shown by the increase in the levels of Cdk5 and its activator P25 in the hippocampus. Furthermore, a Cdk5/P25 inhibitor (roscovitine) or Cdk5 knockdown using small interfering RNA (LVi-Cdk5) exerted neuroprotection by inhibiting abnormal mitochondrial fission through Drp1 phosphorylation at Ser616 and mitochondrial translocation after chronic ethanol exposure. Taken together, the present study demonstrated that inhibition of aberrant Cdk5 activation attenuates hippocampal neuron injury and cognitive deficits induced by chronic exposure to ethanol through Drp1-mediated mitochondrial fission and mitochondrial dysfunction. Interfering with this pathway might serve as a potential therapeutic approach to prevent ethanol-induced neurotoxicity in the brain.

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Acknowledgements

We thank Prof. Jun Liu for providing the HT22 cells.

Funding

The study was supported by the Guangzhou Municipal Science and Technology Project: (grant number: 201904010314) and the National Key R&D Program of China (grant numbers: 2018YFC1314400 and 2018YFC1314401).

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  1. Dandan Liu, Jiande Li, and Xiaoming Rong contributed equally to this work.

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  1. Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Dandan Liu, Jiande Li, Xiaoming Rong, Ying Peng & Qingyu Shen

  2. The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Jie Li & Qingyu Shen

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Dandan Liu, Qingyu Shen, and Ying Peng conceptualized and designed the research. Dandan Liu and Jiande Li performed the experiments. Dandan Liu, Xiaoming Rong, and Jie Li collected and analyzed the data. Dandan Liu and Xiaoming Rong prepared the manuscript. Qingyu Shen, Ying Peng, Jie Li, and Jiande Li critically reviewed the manuscript and approved the final manuscript.

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Liu, D., Li, J., Rong, X. et al. Cdk5 Promotes Mitochondrial Fission via Drp1 Phosphorylation at S616 in Chronic Ethanol Exposure–Induced Cognitive Impairment. Mol Neurobiol 59, 7075–7094 (2022). https://doi.org/10.1007/s12035-022-03008-w

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