PARS2 is a mitochondrial aminoacyl-tRNA synthetase that catalyzes the attachment of proline to its cognate transfer RNA (tRNA-Pro), a critical step in mitochondrial protein synthesis 1. The enzyme functions through a two-step mechanism: proline is first activated by ATP to form Pro-AMP, then transferred to the acceptor end of tRNA-Pro [UniProt]. Loss of PARS2 activity reduces mitochondrial tRNA-Pro aminoacylation, leading to decreased oxidative phosphorylation (OXPHOS) complex protein levels and defective complex assembly 2. Biallelic pathogenic PARS2 variants cause Developmental and Epileptic Encephalopathy-75 (DEE-75), characterized by early-onset refractory infantile spasms, intellectual disability, microcephaly, and cerebral atrophy with hypomyelination 1. Additional features may include lactic acidemia, cardiomyopathy, hearing loss, and ovarian dysfunction 34. Most affected individuals historically died before age 10, though longer survival without cardiac involvement has been documented 13. Recent mechanistic studies reveal that PARS2 deficiency activates the integrated stress response (ISR) pathway through GCN2 kinase, reducing global protein translation via ATF4 activation; genetic suppression of GCN2 or ATF4 reverses developmental delay and seizure phenotypes in disease models 2. These findings suggest targeting ISR as a potential therapeutic approach for PARS2-related disease.