MGME1 (mitochondrial genome maintenance exonuclease 1) is a metal-dependent mitochondria-specific nuclease essential for mitochondrial DNA (mtDNA) maintenance 1. The enzyme exhibits 5'-3' exonuclease activity with preference for single-stranded DNA substrates, particularly those containing 5'-phosphate groups which enhance its DNA-binding and enzymatic activities 2. MGME1 functions in mtDNA repair and replication by processing displaced DNA fragments, Okazaki fragments during lagging strand synthesis, and DNA flaps during base excision repair 2. Structurally, MGME1 utilizes a conserved two-cation-assisted catalytic mechanism for substrate binding and cleavage 1. The enzyme works coordinately with DNA polymerase γ in mtDNA degradation, and absence of MGME1 leads to fragmented mtDNA with unique duplications throughout the genome 3. Pathogenic variants in MGME1 cause mitochondrial DNA maintenance defects (MDMDs), including mitochondrial DNA depletion syndrome 11, resulting in severe clinical phenotypes ranging from ophthalmoplegia to fatal hepatic failure 4. Additionally, MGME1 dysfunction contributes to age-related inflammatory responses through aberrant ribonucleotide incorporation into mtDNA, leading to cytosolic mtDNA release and cGAS-STING pathway activation 5.