Impact of LITAF on Mitophagy and Neuronal Damage in Epilepsy via MCL-1 Ubiquitination

  • CNS Neurosci Ther. 2025 Jan;31(1):e70191. doi: 10.1111/cns.70191.
Fuli Min  1 ,  Zhaofei Dong  2 ,  Shuisheng Zhong  3 ,  Ze Li  1 ,  Hong Wu  1 ,  Sai Zhang  1 ,  Linming Zhang  4 ,  Tao Zeng  1  5
Affiliations
  • 1. Department of Neurology, School of Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
  • 2. Department of Neurology, the Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 3. Department of Neurology, Guangdong Sanjiu Brain Hospital, Guangzhou, China.
  • 4. Department of Neurology, The First Affliated Hospital of Kunming Medical University, Kunming, China.
  • 5. Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
PMID: 39764629 DOI: 10.1111/cns.70191
Abstract

Objective: This study aims to investigate how the E3 ubiquitin Ligase LITAF influences mitochondrial Autophagy by modulating Mcl-1 ubiquitination, and its role in the development of epilepsy.

Methods: Employing single-cell RNA Sequencing (scRNA-seq) to analyze brain tissue from epilepsy patients, along with high-throughput transcriptomics, we identified changes in gene expression. This was complemented by in vivo and in vitro experiments, including protein-protein interaction (PPI) network analysis, western blotting, and behavioral assessments in mouse models.

Results: Neuronal cells in epilepsy patients exhibited significant gene expression alterations, with increased activity in apoptosis-related pathways and decreased activity in neurotransmitter-related pathways. LITAF was identified as a key upregulated factor, inhibiting mitochondrial Autophagy by promoting Mcl-1 ubiquitination, leading to increased neuronal damage. Knockdown experiments in mouse models further confirmed that LITAF facilitates Mcl-1 ubiquitination, aggravating neuronal injury.

Conclusion: Our findings demonstrate that LITAF regulates Mcl-1 ubiquitination, significantly impacting mitochondrial Autophagy and contributing to neuronal damage in epilepsy. Targeting LITAF and its downstream mechanisms may offer a promising therapeutic strategy for managing epilepsy.

Keywords
LPS‐induced TNF‐alpha factor; MCL1; epilepsy; mitochondrial autophagy; neuroprotection; ubiquitination regulation.
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