Human Molecular Genetics Advance Access originally published online on December 20, 2005
Human Molecular Genetics 2006 15(2):363-374; doi:10.1093/hmg/ddi454
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Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase 
associated with progressive external ophthalmoplegia
1Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA and 2Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
* To whom correspondence should be addressed. Tel: +1 9195414792; Fax: +1 9195417613; Email: copelan1{at}niehs.nih.gov
Received October 28, 2005; Accepted December 9, 2005
A number of nuclear mutations have been identified in a variety of mitochondrial diseases including progressive external ophthalmoplegia (PEO), Alpers syndrome and other neuromuscular and oxidative phosphorylation defects. More than 50 mutations have been identified in POLG, which encodes the human mitochondrial DNA (mtDNA) polymerase 
, PEO and Alpers patients. To rapidly characterize the effects of these mutations, we have developed a versatile system that enables the consequences of homologous mutations, introduced in situ into the yeast mtDNA polymerase gene MIP1, to be evaluated in vivo in haploid and diploid cells. Overall, distinct phenotypes for expression of each of the mip1-PEO mutations were observed, including respiration-defective cells with decreased viability, dominant-negative mutant polymerases, elevated levels of mitochondrial and nuclear DNA damage and chromosomal mutations. Mutations in the polymerase domain caused the most severe phenotype accompanied by loss of mtDNA and cell viability, whereas the mutation in the exonuclease domain showed mild dominance with loss of mtDNA. Interestingly, the linker region mutation caused elevated mitochondrial and nuclear DNA damage. The cellular processes contributing to these observations in the mutant yeast cells are potentially relevant to understanding the pathologies observed in human mitochondrial disease patients.
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