The mitochondrial DNA polymerase in health and disease

Abstract

Since mutations in mitochondrial DNA (mtDNA) have been shown to be a cause of many mitochondrial diseases as well as aging, it is important to understand the origin of these mutations and how replication proteins modulate this process. DNA polymerase gamma (pol gamma) is the polymerase that is responsible for replication and repair of mtDNA. Pol gamma has three main roles in mtDNA maintenance and mutagenesis. As the only known DNA polymerase in mitochondria, pol gamma is required for all replication and repair functions and is the main source of errors produced in human mtDNA. Pol gamma is also sensitive to a host of antiviral nucleoside analogs used to treat HIV-1 infections, which can cause an induced mitochondrial toxicity. Finally, the gene for pol gamma, POLG, is a genetic locus for several mitochondrial disease with over 150 genetic mutations currently identified.

Figure 1

Schematic diagram of human pol γ protein showing the location of amino acid substitutions resulting from disease and polymorphism mutations. Disease substitutions above the line that are not boxed are associated with Alpers and myocerebralhepatopathy syndrome, while boxed substations above the line are associated with ataxia-neuropathy syndromes. Mutations below the line are associated with various forms of progressive external ophthalmoplegia where boxed mutations are autosomal dominant PEO substitutions. The Δ(CAG)_n repeat is associated with male infertility or idiopathic Parkinsons disease. Arrows and substitutions with an asteric depict the non-synonymous polymorphic amino acid changes.