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.
Highlights
Mitochondria are the sites of vital cellular functions such as the synthesis of the cellular energy by oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, amino acid, and heme biosynthesis [1]
We found that 56 of the 102 yeast strains (54.9%) that lost their mitochondrial DNA (mtDNA) were associated with deletions of genes which function in mitochondrial protein synthesis
To gain insights into the genetic contribution of nuclear genes to maintaining mitochondrial genome stability, we have taken a systematic approach to the identification of nuclear genes by screening a set of yeast deletion strains demonstrating a complete loss of mtDNA
Summary
Mitochondria are the sites of vital cellular functions such as the synthesis of the cellular energy by oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, amino acid, and heme biosynthesis [1]. MtDNA missense mutations have been associated with ophthalmological and neurological diseases known as Leber’s Hereditary Optic Neuropathy (LHON), and Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP). Transfer RNA mutations are known for Myoclonic Epilepsy and Ragged-Red Fiber Disease (MERRF); Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Symptoms (MELAS); and Maternally Inherited Myopathy and Cardiomyopathy (MMC). Another frequently described pathology associated with reduced mtDNA content is mtDNA depletion syndromes (MDS), a group of severe diseases of childhood. Over 100 heritable disorders have been attributed to defects in mitochondrial function in humans, and new mitochondrial disease genes are still being identified [4]
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