A mechanistic view of human mitochondrial DNA polymerase γ: Providing insight into drug toxicity and mitochondrial disease

Mitochondrial DNA polymerase gamma (Pol γ) is the sole polymerase responsible for replication of the mitochondrial genome. The study of human Pol γ is of key importance to clinically relevant issues such as nucleoside analog toxicity and mitochondrial disorders such as progressive external ophthalmoplegia. The development of a recombinant form of the human Pol γ holoenzyme provided an essential tool in understanding the mechanism of these clinically relevant phenomena using kinetic methodologies. This review will provide a brief history on the discovery and characterization of human mitochondrial DNA polymerase γ, focusing on kinetic analyses of the polymerase and mechanistic data illustrating structure–function relationships to explain drug toxicity and mitochondrial disease.