A p.R369G POLG2 mutation associated with adPEO and multiple mtDNA deletions causes decreased affinity between polymerase γ subunits

► Human mtDNA pol γ is the sole enzyme which replicates the mitochondrial genome. ► It compromises a catalytic subunit and a p55 accessory subunit encoded by POLG2. ► Mutations in the POLG2 gene are rarely described in human disease. ► A p.R369G POLG2 mutation impairs binding of p55 to the catalytic p140 subunit. ► Insensitivity to NEM inhibition implies a new molecular mechanism for this mutation.