POLG and External ophthalmoplegia: This study shows that mitochondrial entry of the replicative polymerase PolgA is regulated by ubiquitylation by the E3 ligase MITOL; however, by manipulating their ubiquitylation status, some progressive external ophthalmoplegia mutants whose PolgA is polyubiquitylated and cannot enter the mitochondrion can be reactivated and hence become functionally active.