Thanks to the similarity between human Pol gamma and Mip1, yeast has been used to validate the role of human putative pathological mutations, to understand the biochemical consequences associated to these mutations, to study the pharmacogenetics of drugs such as valproate and stavudine, and to find mechanisms able to rescue the detrimental effects of Mip1 MK-4827mutations. Since a therapy has not been yet developed for mitochondrial diseases caused by POLG mutations, a major goal of the research involving yeast/animal models is to find new strategies to rescue the pathological phenotypes associated to these mutations. Yeast is a suitable model organism to study the effects of nuclear mutations affecting mtDNA stability, thanks to its ability to survive in absence of a functional mitochondrial genome and to the possibility to easily analyze mtDNAMLN4924 Metabolic Enzyme/Protease inhibitormutability. Yeast cells containing deletions-carrying mtDNA, called rho-, or cells which have completely lost mtDNA, called rho0, are respiratory deficient and produce colony of small size, called petite. rho2 cells, which arise more frequently than rho0 cells, retain only small fragments of wt mtDNA, from 30% to less than 1%. Although the mechanisms thanks to which rho2 mutations arise are not fully know, analysis of the regions flanking the deleted regions suggest that mtDNA of some of these rho2 cells derives from recombination between direct repeats flanking the deleted region with consequent excision. In addition, deletions do not occur randomly at all. As a matter of fact, some fragments, encompassing COB, COX2 and COX3 genes, are most frequently retained. These large deletions make mtDNA irreversibly unfunctional. In S. cerevisiae, petite mutants arise spontaneously with high frequency. The frequency of petite mutants is a measure of mtDNA extended mutability and is an index of mtDNA instability. Extended mutability is indeed a series of large deletions that arise spontaneously, and partially randomly, in the mtDNA, without involvement of point mutations. Mutations in a large group of nuclear genes, encoding for proteins directly or indirectly involved in mtDNA replication, recombination, stability and maintenance produce increase of petite mutability. mtDNA point mutations can be also easily measured as frequency of spontaneous mutants resistant to erythromycin, an antibiotic that inhibits mitochondrial but not cytoplasmic translation. In fact, resistance to erythromycin is acquired through specific transversions or transitions in the mitochondrial gene encoding the 21 S rRNA, in particular at 1950, 1951, 1952 and 3993 positions. EryR mutants arise spontaneously approximately at a frequency of 1027–1028.