All the residues that have significant contribution to the interactions with the active site are evolutionarily conserved and some are sites for pathogenic mutations as well . A previous study on a mutation of R853 (R853A) , which is linked to diseases such as Progressive External Opthalmoplegia (PEO) indicates that the mutation changes structural and dynamic features of the protein, which could render it catalytically incompetent, providing a possible explanation for the observed experimental results. Other residues that are a common mutagenesis sites are T849, E895, K925, R943, and K1191 leading to Alpers and other Infantile Hepatocerebral Syndromes with mt DNA depletion, whereas R869 and R943 are also related to PEO.