PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic...

PARS2, encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability. While genetic associations between PARS2 and DEE have been established, the underlying molecular mechanisms remain poorly understood. This study integrates genetic analyses of clinical cases of infantile epileptic spasms syndrome (IESS) with functional assessments in PARS2-deficient animal models and cell models to elucidate these mechanisms. Our findings indicate that PARS2 deficiency disrupts mitochondrial integrity and impairs oxidative phosphorylation, resulting in elevated intracellular calcium levels. This calcium overload activates CaMKK2-AMPK-Drp1 signaling, promoting excessive mitochondrial fission and PINK1-Parkin-mediated mitophagy, ultimately leading to degradation of GPX4 and subsequent ferroptosis. Notably, pharmacological inhibition of Drp1 using Mdivi-1 successfully rescued mitochondrial fragmentation and mitigated ferroptosis. These results unveil a novel calcium-mitophagy-ferroptosis pathway as a crucial mechanism in PARS2-related DEE and propose a potential therapeutic strategy for DEE.