Abstract
Mitochondrial dysfunction contributes critically to epileptogenesis. Therefore, identifying key mitochondrial function-associated genes in epilepsy may provide novel insights into its pathogenesis. We employed expression quantitative trait loci (eQTLs) and Mendelian randomization analyses to assess mitochondrial-epilepsy causality, with leave-one-out validation confirming the reliability and directionality of the results. The results revealed that hydroxyacylglutathione hydrolase (HAGH), oxysterol-binding protein-related protein 1A (OSBPL1A) and pantothenate kinase 2 (PANK2) were pivotal epileptogenic genes. HAGH modulates the mechanistic target of rapamycin complex 1 (mTORC1) signaling and fatty acid metabolism pathways. OSBPL1A mediates apoptotic and reactive oxygen species (ROS) pathways. PANK2 regulates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling and Notch signaling cascades. Additionally, these genes participate in inflammatory pathways, including T cell receptor (TCR), mitogen-activated protein kinase (MAPK), and tumor necrosis factor (TNF) signaling. We demonstrated that HAGH, OSBPL1A, and PANK2 constitute core pathogenic mechanisms in epilepsy. These genes potentially govern epileptogenesis through mitochondrial regulation via neuroinflammatory, immunomodulatory, and apoptotic pathways. Our findings provide a foundation for investigating epileptogenesis, discovering therapeutic targets, and identifying prognostic biomarkers.