Yeast Nuclear Genes for mtDNA Maintenance

The budding yeast Saccharomyces cerevisiae is a particularly suitable organism for identifying nuclear genes involved in the maintenance of the mitochondrial genome. Indeed, S. cerevisiae can grow and divide in the absence of respiration and, moreover, without mitochondrial DNA. In addition, the complete sequences of the nuclear and mitochondrial genomes of S. cerevisiae are available (1 ,2 ), classical genetics has extensively been carried out, and yeast genomics is exponentially developing. Based on the Yeast Proteome Database (YPD) (http://www.proteome.com/), 464 yeast genes encode mitochondrial proteins and there are probably many more. However, our knowledge concerning the genes that are specifically involved in the maintenance of the yeast mitochondrial genome remains very incomplete. A specific feature of S. cerevisiae is that during vegetative growth, this yeast produces at highfrequency mutant cells that contain large deletions of mitochondrial DNA (for a review, see ref. 3 ). These cells which were initially called “petites” because they make small colonies (4 ) are also known as rho- mutants. They have an irreversible loss of respiration, do not grow on glycerol, and exhibit non-Mendelian inheritance. Cytoplasmic petites that are completely devoid of mitochondrial DNA are called rho⁰ . Cytoplasmic petites are to be distinguished from Pet mutants, which do not grow on glycerol and exhibit classical Mendelian inheritance (5 ). A minority of Pet mutants are not able to maintain their mitochondrial DNA (for a review, see ref. 6 ). Some Pet rho⁰ mutants have mutations in mitochondrial proteins directly involved in mitochondrial DNA transactions, such as the yeast mitochondrial DNA polymerase MIP1 (7 ), the single-stranded DNA-binding protein RIM1 (8 ), or the RNA polymerase RPO41 (9 ). Others encode cytoplasmic or nuclear proteins that control the synthesis, or the flux, of metabolites necessary for mitochondrial DNA synthesis, such as the thymidylate kinase (10 ), thymidylate synthase (10 ), or subunits of the ribonucleotide reductase (11 ,12 ). Finally, some genes encode proteins shared by the nucleus and the mitochondrion such as the CDC9 ligase (13 ,14 ). For more detailed information, we wish to refer to the remarkable review by Contamine and Picard (6 ).