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ATF5 Attenuates Apoptosis in Hippocampal Neurons with Seizures Evoked by Mg2+-Free Medium via Regulating Mitochondrial Unfolded Protein Response

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Abstract

The mitochondrial unfolded protein response (mtUPR)-a stress response pathway for maintaining protein homeostasis-is critical in seizures-induced neuronal injury. The activating transcription factor 5 (ATF5) regulates mtUPR; however, whether ATF5-regulated mtUPR has a role in neuronal injury in epilepsy remains uncertain. Here, we investigated the effects of ATF5-regulated mtUPR on neuronal injury in hippocampal neurons with seizures evoked by Mg2+-free medium. HSP60 and ClpP, key proteins of mtUPR, were upregulated, indicating mtUPR activation. ATF5 overexpression by lentiviral vector infection potentiated mtUPR, whereas ATF5 downregulation by lentiviral vector infection attenuated this response. Moreover, ATF5 overexpression elevated mitochondrial membrane potential and reduced reactive oxygen species (ROS) generation, suggesting that ATF5 overexpression protected mitochondrial homeostasis, while ATF5 downregulation had the opposite effect. ATF5 overexpression also reversed Bcl2 downregulation and Bax upregulation and attenuated seizures-induced neuronal apoptosis, while ATF5 downregulation aggravated the injury. Our study demonstrates that ATF5 attenuates seizures-induced neuronal injury, possibly by regulating mtUPR pathways, to prevent mitochondrial dysfunction.

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Data Availability

All data generated by the current study are available upon reasonable request.

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Acknowledgments

We acknowledge the support of the Translational Medicine Platform of Academy of Medical Sciences, Zhengzhou University.

Funding

This work was supported by the National Natural Science Foundation of China (81971214, 81701272), and Provincial Ministry Co-construction Project from Medical Scientific and Technological Research Program of Henan Province (SB201902011).

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Authors and Affiliations

  1. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, China

    Xiaoyi Wang & Cui Wang

  2. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Xiaomeng Yu, Yujuan Li, Fengxia Liu, Liyuan Du & Nanchang Xie

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  1. Xiaoyi Wang
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Contributions

XYW, XMY, and LYD performed the experiments. XYW, YJL, and FXL analyzed the data. The first draft of the manuscript was written by XYW. CW and NCX contributed to the study conception and design, and revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Nanchang Xie or Cui Wang.

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The study was approved by the ethics committee of Zhengzhou University, and the experiment was conducted in strict accordance with international standards.

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Wang, X., Yu, X., Li, Y. et al. ATF5 Attenuates Apoptosis in Hippocampal Neurons with Seizures Evoked by Mg2+-Free Medium via Regulating Mitochondrial Unfolded Protein Response. Neurochem Res 48, 62–71 (2023). https://doi.org/10.1007/s11064-022-03702-0

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