Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability

Abstract

Mitochondrial DNA (mtDNA) maintenance is critical for oxidative phosphorylation (OXPHOS) since some subunits of the respiratory chain complexes are mitochondrially encoded. Pathological mutations in nuclear genes involved in the mtDNA metabolism may result in a quantitative decrease in mtDNA levels, referred to as mtDNA depletion, or in qualitative defects in mtDNA, especially in multiple deletions. Since, in the last decade, most of the novel mutations have been identified through whole-exome sequencing, it is crucial to confirm the pathogenicity by functional analysis in the appropriate model systems. Among these, the yeast Saccharomyces cerevisiae has proved to be a good model for studying mutations associated with mtDNA instability. This review focuses on the use of yeast for evaluating the pathogenicity of mutations in six genes, MPV17/SYM1, MRM2/MRM2, OPA1/MGM1, POLG/MIP1, RRM2B/RNR2, and SLC25A4/AAC2, all associated with mtDNA depletion or multiple deletions. We highlight the techniques used to construct a specific model and to measure the mtDNA instability as well as the main results obtained. We then report the contribution that yeast has given in understanding the pathogenic mechanisms of the mutant variants, in finding the genetic suppressors of the mitochondrial defects and in the discovery of molecules able to improve the mtDNA stability.

Yeast Chromatin Mutants Reveal Altered mtDNA Copy Number and Impaired Mitochondrial Membrane Potential

“…The number of mtDNA molecules depends on different factors such as growth conditions (carbon source, temperature), ploidy (haploid, diploid), ROS concentration and oxidative stress, and it has been determined that a single yeast cell can harbour between 10–50 to 200 mtDNA copies per nuclear genome [ 3 , 70 , 71 , 72 ]. With the progression of CLS, alterations were detected in both the number and the morphology of mitochondria, the mitochondrial network underwent extensive fragmentation, and mitochondrial filaments disappeared [ 11 ].…”

“…Mitochondria are multifunctional cellular organelles with an endosymbiotic origin that are crucially important for eukaryotic cells and are intrinsically connected with ageing [ 1 , 2 , 3 ]. Most of the present knowledge of how mitochondria work was initially discovered using Saccharomyces cerevisiae, starting with pioneer works about 60 years ago [ 4 ].…”

AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease

“…Mitochondrial DNA (mtDNA) is independent of nuclear DNA and encodes subunits involved in the mitochondrial respiratory chain, which mediates to proceed oxidative phosphorylation (OXPHOS), including ND1-6, ND4L, COX I-III, cyt-b, ATPase6 and ATPase8 [6]. mtDNA replication is closely related to mitochondrial metabolism [7,8].…”

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

“…mtDNA possesses its own transcriptional and translational system and encodes 2 rRNAs, 22 tRNAs, and 13 polypeptides. These polypeptides include ND1-6, ND4L, COXⅠ-Ⅲ, cyt-b, ATPase6, and ATPase8, which are involved in the composition of the mitochondrial respiratory complexes to maintain the integrity of the electron transport chain (ETC) and the stability of oxidative phosphorylation (OXPHOS) [ 3 ]. The functioning of OXPHOS provides physiologically required energy to cells and organs, and the ETC is the main source of reactive oxygen species (ROS) production.…”