In 1890, the German scientist Altmann observed mitochondria in tissue sections from mouse liver and coined the term Elementarorganismen, as he thought he had found free-living organisms inside the nucleated cell (Altmann, 1890). We know today that mitochondria are not independent at all, despite having their own genome. Instead, they rely on a large number of nuclear genes for their function (Falkenberg et al., 2007). Mammalian mitochondrial DNA (mtDNA) is a circular, double-stranded DNA molecule of ?16 kb that only encodes 13 proteins, essential subunits of the oxidative phosphorylation system. The remaining ?1500 mitochondrial proteins are encoded in the nucleus, including all proteins needed for replication and expression of the small mtDNA genome (Falkenberg et al., 2007). In this issue of Cell, Lee et al. (2009) present the structure of the human mitochondrial DNA polymerase (POLγ), a nuclear-encoded heterotrimeric enzyme that replicates the mtDNA genome. The structure of POLγ provides insight into the function of a unique spacer domain involved in processivity and subunit interaction. Mutations in the POLγA subunit are a frequent cause of disease, and the Lee et al. study now provides a basis for classifying and understanding such mutations. Finally, the structure will facilitate the development of antiviral nucleoside analogs that do not affect mtDNA maintenance.
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