Global Genetic Determinants of Mitochondrial DNA Copy Number

Abstract

Many human diseases including development of cancer is associated with depletion of mitochondrial DNA (mtDNA) content. These diseases are collectively described as mitochondrial DNA depletion syndrome (MDS). High similarity between yeast and human mitochondria allows genomic study of the budding yeast to be used to identify human disease genes. In this study, we systematically screened the pre-existing respiratory-deficient Saccharomyces cerevisiae yeast strains using fluorescent microscopy and identified 102 nuclear genes whose deletions result in a complete mtDNA loss, of which 52 are not reported previously. Strikingly, these genes mainly encode protein products involved in mitochondrial protein biosynthesis process (54.9%). The rest of these genes either encode protein products associated with nucleic acid metabolism (14.7%), oxidative phosphorylation (3.9%), or other protein products (13.7%) responsible for bud-site selection, mitochondrial intermembrane space protein import, assembly of cytochrome-c oxidase, vacuolar protein sorting, protein-nucleus import, calcium-mediated signaling, heme biosynthesis and iron homeostasis. Thirteen (12.7%) of the genes encode proteins of unknown function. We identified human orthologs of these genes, conducted the interaction between the gene products and linked them to human mitochondrial disorders and other pathologies. In addition, we screened for genes whose defects affect the nuclear genome integrity. Our data provide a systematic view of the nuclear genes involved in maintenance of mitochondrial DNA. Together, our studies i) provide a global view of the genes regulating mtDNA content; ii) provide compelling new evidence toward understanding novel mechanism involved in mitochondrial genome maintenance and iii) provide useful clues in understanding human diseases in which mitochondrial defect and in particular depletion of mitochondrial genome plays a critical role.

Systematic analysis of nuclear gene function in respiratory growth and expression of the mitochondrial genome in S. cerevisiae

“…Consistently, we found that 38 deletion mutants lacking genes required for mitochondrial protein synthesis failed to maintain a functional [ARG8 m ] genome -this is by far the largest group of genes required for this process. This is in good agreement with previous studies, which also reported that mitochondrial protein synthesis is particularly important for mtDNA maintenance [18,71]. Our results suggest that mitochondrial translation is required for mitochondrial genome maintenance even when respiratory activity is not required.…”

Mitochondrial DNA: A disposable genome?

“…A systematic analysis in yeast revealed 102 ORFs whose deletion led to the loss of mtDNA. Remarkably, 55% of those ORFs were associated with biosynthesis of mitochondrial proteins [32]. In humans, sex-specific quantitative trait loci for mtDNA content have been identified on chromosomes 1, 2 and 3 [33].…”

Mitochondrial determinants of cancer health disparities

“…A low mtDNA content can be caused by mutations in the p53 gene, the POLG gene, and the gene for the mitochondrial transcription factor, TFAM [189, 338–340]. In a yeast screen designed to identify nuclear genes involved in the maintenance of mtDNA, Zhang and Singh identified more than 50 human homologs whose inactivation caused depletion of mtDNA [414]. It is likely that germline variants or somatic mutations in these genes alter mtDNA content and may promote apoptotic resistance and risk of cancers.…”