The CoQ biosynthetic di-iron carboxylate hydroxylase COQ7 is inhibited by in vivo metalation with manganese but remains function by metalation with cobalt

COQ7 is a mitochondrial hydroxylase that catalyzes the penultimate step of the biosynthesis of coenzyme Q (CoQ; ubiquinone). CoQ is an obligate component of the mitochondrial electron transport chain and an antioxidant. CoQ deficiencies due to mutations in CoQ biosynthetic enzymes are severe genetic disorders often manifesting as mitochondrial disease syndrome. COQ7 is part of the relatively rare class of di-iron carboxylate enzymes, which carry out a wide range of reactions. In a previous study we described how COQ7 activity is inhibited in mammalian cells after treatment with iron chelating agents. Here, we report that manganese exposure of mouse cells leads to decreased COQ7 activity and resulting CoQ deficiency, which might participate in manganese toxicity. We find that the presence of cobalt can interfere with the inhibition of COQ7 by manganese. We present evidence that both manganese inhibition and cobalt interference are the result of metal exchange at the di-iron active site of COQ7. We present findings that suggest that 1) cobalt has greater affinity for the active site of COQ7 than both iron and manganese and, 2) that iron replacement by cobalt at the active site preserves catalytic activity.