The most convincing evidence for a central role of Top3α in mtDNA maintenance comes from the fact that certain compound heterozygotic mutations in Top3α can give rise to progressive external ophthalmoplegia (PEO), a mitochondrial DNA maintenance syndrome caused by pathological mutations in the mitochondrial replicative helicase TWNK and DNA polymerase γ [59]. Here, TOP3A is linked to progressive external ophthalmoplegia.