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Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations

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Abstract

DNA polymerase γ (pol γ), encoded by POLG, is responsible for replicating human mitochondrial DNA. About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the mutations are described in single citations with no genotypic family history, it is important to ascertain which mutations cause or contribute to mitochondrial disease. The vast majority of data about POLG mutations has been generated from biochemical characterizations of recombinant pol γ. However, recently, the study of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models provides important in vivo evidence for the role of POLG mutations in disease. Also, the published 3D-structure of the human pol γ assists in explaining some of the biochemical and genetic properties of the mutants. This review summarizes the current evidence that identifies and explains disease-causing POLG mutations.

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Acknowledgments

We thank Margaret Humble for maintaining and updating the Pol Gamma mutation database (http://tools.niehs.nih.gov/polg) and for her help in generating Fig. 3 of this review. We thank Dr. Rachelle Bienstock for help with the structural images in this review. We also thank Drs. Matthew Young and Rajesh Kasiviswanathan for the comments and suggestions from their critical reading of this manuscript. This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES 065078).

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  1. Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Dr., Bldg. 101, Rm. E316, Research Triangle Park, NC, 27709, USA

    Jeffrey D. Stumpf & William C. Copeland

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  1. Jeffrey D. Stumpf
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  2. William C. Copeland
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Correspondence to William C. Copeland.

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Stumpf, J.D., Copeland, W.C. Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations. Cell. Mol. Life Sci. 68, 219–233 (2011). https://doi.org/10.1007/s00018-010-0530-4

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  • DOI: https://doi.org/10.1007/s00018-010-0530-4

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