Abstract
The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast.
Highlights
Mitochondria are dynamic organelles that supply most of the ATP needed to sustain the different energy-demanding activities of eukaryotic cells
One of the unexpected finding to have emerged from the functional analyses of pet mutants is the large extent to which expression of mitochondrial genes depends on mRNA-specific factors encoded in nuclear DNA
This study demonstrated that the biochemical phenotype produced by the UQCC2 mutation is similar to that reported in yeast [57], as cytochrome b synthesis and stability was decreased in the patient’s fibroblasts [111]
Summary
Mitochondria are dynamic organelles that supply most of the ATP needed to sustain the different energy-demanding activities of eukaryotic cells Their ATP generating pathway consists of the oxphos complexes—four hetero-oligomeric complexes that make up the electron transfer chain plus the ATP synthase. One of the unexpected finding to have emerged from the functional analyses of pet mutants is the large extent to which expression of mitochondrial genes depends on mRNA-specific factors encoded in nuclear DNA. Mutations presenting different clinical phenotypes were reported in nuclear genes that code for protein subunits of the ATP synthase and factors that function as chaperones during its assembly [5,6,7] and enzymes of biosynthetic pathways for heme a [8] and coenzyme Q [9]. When the human genes do not complement the respective yeast mutant, it is still possible to evaluate the pathogenicity of a given mutation by constructing an allele with the corresponding change in the yeast gene
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