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

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.

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