DNA polymerase gamma is the only DNA polymerase found in the mitochondria and is responsible for maintaining the integrity of the mitochondrial genome by mtDNA replication and repair. DNA polymerase gamma is composed of a catalytic subunit (POLG1) and an accessory subunit (POLG2). POLG2 enhances the affinity of the DNA polymerase gamma to bind to DNA. Mutations in POLG2 lead to a failure to enhance the DNA-binding strength which stalls the DNA replication fork causing mtDNA deletions to arise. The progressive accumulation of the mtDNA deletions causes cytochrome c oxidase (COX) deficiency in muscle fibers, primarily external eye muscles and skeletal muscle. Autosomal dominant progressive external ophthalmoplegia with mtDNA deletions (PEO4) is characterized by adult-onset weakness of the external eye muscles (leading to ptosis), mild weakness of facial muscles and exercise intolerance.