POLG2 is the accessory subunit of mitochondrial DNA polymerase gamma, essential for mtDNA replication and maintenance 1. As a homodimeric protein, POLG2 enhances the catalytic activity and processivity of the POLG catalytic subunit through allosteric regulation and increased DNA template interactions 2. POLG2 possesses dual functionality: it augments processive DNA synthesis by POLG while also directly binding DNA in both dimeric and oligomeric forms, with structure-specific roles targeting forked DNA structures resembling the mitochondrial D-loop 2. Pathogenic variants in POLG2 cause mitochondrial DNA maintenance defects (MDMDs), resulting in either mtDNA depletion or accumulation of multiple deletions 1. Clinical presentations are clinically heterogeneous: biallelic mutations cause severe infantile-onset hepatic failure with mtDNA depletion syndrome, while heterozygous mutations present with adult-onset progressive external ophthalmoplegia, cerebellar ataxia, parkinsonism, and cognitive decline 3. Recent zebrafish polg2 knockout models recapitulate human POLG-related phenotypes including mtDNA depletion, mitochondrial dysfunction, and reduced respiration 4. Clinically, perampanel demonstrated efficacy in POLG2-related epilepsies, achieving >90% seizure reduction in some patients 5, suggesting potential for targeted therapeutic intervention in POLG2-linked disease.