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TRAK1-Mediated Abnormality of Mitochondrial Fission Increases Seizure Susceptibility in Temporal Lobe Epilepsy

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Abstract

Mitochondrial dysfunction is closely related to the occurrence of epilepsy. Homeostasis of mitochondrial fusion and division can alleviate mitochondrial dysfunction. The trafficking kinesin protein 1 (TRAK1) is a key regulator of mitochondrial movement and regulates mitochondrial fusion-fission balance. The pathogenic variants in TRAK1 result in the severe neurodevelopmental disorders. However, the role of TRAK1 in epilepsy remains unclear. In the present study, we report that TRAK1 has a crucial function in regulation of epileptogenesis in temporal lobe epilepsy (TLE). TRAK1 expression is decreased in the patient specimens and animal model of TLE. Knockdown of TRAK1 causes an increase in mitochondrial fission factor (MFF) in vitro and the susceptibility to seizures in vivo. Exogenous overexpression of TRAK1 can rescue the dysfunction caused by TRAK1 knockdown. These findings provide new insights into the fundamental mechanisms of TRAK1 in TLE and have important implications for understanding and treating TLE via targeting mitochondrion.

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Acknowledgments

We sincerely thank the patients and their families for their participation and support in this study.

Funding

This work was supported by the National Natural Science Foundation of China (NO. 81471322, 81601132).

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Author notes

  1. Hao Wu and Yong Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, 710061, Shanxi, China

    Hao Wu, Yong Liu, Huanfa Li, Changwang Du, Kuo Li, Shan Dong, Qiang Meng & Hua Zhang

  2. Center of Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, 710061, Shanxi, China

    Hao Wu & Hua Zhang

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  1. Hao Wu
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Correspondence to Qiang Meng or Hua Zhang.

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All procedures performed in studies involving animals were approved by the Ethics Committee of Fourth Military Medical University and Xi’an Jiaotong University (Ethics and Science # G-83) in full accordance with the ethical guidelines of the National Institutes of Health for the care and use of laboratory animals.

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Wu, H., Liu, Y., Li, H. et al. TRAK1-Mediated Abnormality of Mitochondrial Fission Increases Seizure Susceptibility in Temporal Lobe Epilepsy. Mol Neurobiol 58, 1237–1247 (2021). https://doi.org/10.1007/s12035-020-02175-y

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