Rolling-Circle Replication in Mitochondrial DNA Inheritance: Scientific Evidence and Significance from Yeast to Human Cells

Ling, Feng; Yoshida, Minoru

doi:10.3390/genes11050514

Cited by 12 publications

(15 citation statements)

References 105 publications

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“…Interestingly, rolling circle replication can apparently be induced in mtDNAs of human cells through treatment with H 2 O 2 (a ROS; Ling et al . 2016; Ling and Yoshida 2020), indirectly supporting the link between rolling circle replication and oxidative stress in C. elegans mtDNAs. Assays with human Pol γ in vitro reveal the polymerase is particularly prone to misincorporations leading to AT→GC and CG→TA transitions (Longley et al .…”

Section: Resultsmentioning

confidence: 94%

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Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Waneka

Svendsen

Havird

et al. 2021

Preprint

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Rapid mutation rates are typical of mitochondrial genomes (mtDNAs) in animals, but it is not clear why. The difficulty of obtaining measurements of mtDNA mutation that are not biased by natural selection has stymied efforts to distinguish between competing hypotheses about the causes of high mtDNA mutation rates. Several studies which have measured mtDNA mutations in nematodes have yielded small datasets with conflicting conclusions about the relative abundance of different substitution classes (i.e. the mutation spectrum). We therefore leveraged Duplex Sequencing, a high-fidelity DNA sequencing technique, to characterize de novo mtDNA mutations in Caenorhabditis elegans. This approach detected nearly an order of magnitude more mtDNA mutations than documented in any previous nematode mutation study. Despite an existing extreme AT bias in the C. elegans mtDNA (75.6% AT), we found that a significant majority of mutations increase genomic AT content. Compared to some prior studies in nematodes and other animals, the mutation spectrum reported here contains an abundance of CGAT transversions, supporting the hypothesis that oxidative damage may be a driver of mtDNA mutations in nematodes. Further, we found an excess of GT and CT changes on the coding DNA strand relative to the template strand, consistent with increased exposure to oxidative damage. Analysis of the distribution of mutations across the mtDNA revealed significant variation among protein-coding genes and as well as among neighboring nucleotides. This high-resolution view of mitochondrial mutations in C. elegans highlights the value of this system for understanding relationships among oxidative damage, replication error, and mtDNA mutation.

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Section: Resultsmentioning

confidence: 94%

“…Interestingly, rolling circle replication can apparently be induced in mtDNAs of human cells through treatment with H2O2 (a ROS; Ling et al 2016;Ling and Yoshida 2020), indirectly supporting the link between rolling circle replication and oxidative stress in C. elegans mtDNAs.…”

Section: Stranded Damagementioning

confidence: 85%

Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Waneka

Svendsen

Havird

et al. 2021

Preprint

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“…In many species including S. cerevisiae, aging damages mtDNA, possibly through an excess in ROS that in turn increases activity of proteins that promote mtDNA recombination. Then mutations accumulate damaging mitochondria irreversibly in a "vicious cycle" [55,56].…”

Section: Discussionmentioning

confidence: 99%

“…This is not the only mechanism accelerating electron flow, as other proton sinks such as uncoupling proteins are differentially expressed upon exposure to stress [31]. A second mechanism promoting physiological uncoupling, where branched respiratory chains differentially express their alternative redox enzymes such as alternative oxidase (AOX) or NADH dehydrogenases type 2 (NDH2), in order to increase electron flux in the respiratory chain either at the beginning of the stationary phase or when the cell is subjected to stress [56,57].…”

Section: Discussionmentioning

confidence: 99%

Coupling/Uncoupling Reversibility in Isolated Mitochondria from Saccharomyces cerevisiae

Morales-García

Ricardez-García

Castañeda-Támez

et al. 2021

Life

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The yeast Saccharomyces cerevisiae uses fermentation as the preferred pathway to obtain ATP and requires the respiratory chain to re-oxidize the NADH needed for activity of Glyceraldehyde-3-phosphate. This process is favored by uncoupling of oxidative phosphorylation (OxPhos), which is at least partially controlled by the mitochondrial unspecific pore (ScMUC). When mitochondrial ATP synthesis is needed as in the diauxic phase or during mating, a large rise in Ca2+ concentration ([Ca2+]) closes ScMUC, coupling OxPhos. In addition, ScMUC opening/closing is mediated by the ATP/ADP ratio, which indicates cellular energy needs. Here, opening and closing of ScMUC was evaluated in isolated mitochondria from S. cerevisiae at different incubation times and in the presence of different ATP/ADP ratios or varying [Ca2+]. Measurements of the rate of O2 consumption, mitochondrial swelling, transmembrane potential and ROS generation were conducted. It was observed that ScMUC opening was reversible, a high ATP/ADP ratio promoted opening and [Ca2+] closed ScMUC even after several minutes of incubation in the open state. In the absence of ATP synthesis, closure of ScMUC resulted in an increase in ROS.

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“…Yeast mtDNA is rich in AT-segments, especially in the intergenic regions, with small regions rich in GC-segments, among which four copies of regions called ori initially associate with mtDNA replication [ 51 , 52 ]. Until now, several hypotheses have been proposed in order to explain the mechanisms of mtDNA replication: according to the most recent findings, S. cerevisiae mtDNA should be replicated through a rolling circle mechanism in which the leading strand is primed by recombinational structures, and which results in the coexistence of circular molecules and linear concatemers of DNA [ 53 , 54 , 55 , 56 ] (reviewed in [ 57 , 58 ]).…”

Section: Introductionmentioning

confidence: 99%

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

Gilea

Berti

Magistrati

et al. 2021

Genes

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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.

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Rolling-Circle Replication in Mitochondrial DNA Inheritance: Scientific Evidence and Significance from Yeast to Human Cells

Cited by 12 publications

References 105 publications

Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Coupling/Uncoupling Reversibility in Isolated Mitochondria from Saccharomyces cerevisiae

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

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