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DNA polymerase γ (pol γ) is responsible for replication and repair of mitochondrial DNA (mtDNA). Over 150 mutations in  POLG  (which encodes pol γ) have been discovered in patients with mitochondrial disorders including Alpers, progressive external ophthalmoplegia and ataxia-neuropathy syndrome. However, the severity and dominance of many  POLG  disease-associated mutations are unclear, because they have been reported in sporadic cases. To understand the consequences of pol γ disease-associated mutations  in vivo , we identified dominant and recessive changes in mtDNA mutagenesis, depletion and mitochondrial dysfunction caused by 31 mutations in the conserved regions of the gene,  MIP1 , which encodes the  Saccharomyces cerevisiae  ortholog of human pol γ. Twenty  mip1  mutant enzymes were shown to disrupt mtDNA replication and may be sufficient to cause disease. Previously uncharacterized sporadic mutations, Q308H, R807C, G1076V, R1096H and S1104C, caused decreased polymerase activity leading to mtDNA depletion and mitochondrial dysfunction. We present evidence showing a limited role of point mutagenesis by these  POLG  mutations in mitochondrial dysfunction and disease progression. Instead, most mitochondrial defective  mip1  mutants displayed reduced or depleted mtDNA. We also determined that the severity of the phenotype of the  mip1  mutant strain correlates with the age of onset of disease associated with the human ortholog. Finally, we demonstrated that increasing nucleotide pools by overexpression of ribonucleotide reductase (RNR1) suppressed mtDNA replication defects caused by several dominant  mip1  mutations, and the orthologous human mutations revealed severe nucleotide binding defects.

mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae