Known Unknowns of Mammalian Mitochondrial DNA Maintenance

Pohjoismäki, Jaakko L. O.; Forslund, Josefin M. E.; Goffart, Steffi; Torregrosa‐Muñumer, Rubén; Wanrooij, Sjoerd

doi:10.1002/bies.201800102

Cited by 18 publications

(13 citation statements)

References 99 publications

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“…Here we propose a model of the asymmetric DNA strand inheritance, which provides a simple explanation to the observed highly biased pattern of mutations in vertebrate mtDNA (Figure 3). Our model is consistent with the strand-asynchronous models of mtDNA replication: SDM and RITOLS (Falkenberg 2018;Holt and Reyes 2012;Pohjoismaki et al 2018), but contain several new, important features which apparently have not been discussed before. In this model we suggest that the singlestranded H-strand, anchored to inner membrane through specific interactions with Control Region or probably D-loop structure, would replicate in uninterrupted manner to make new DNA progeny (containing parental H-strand and nascent L-strand) (Figure 3, step 6).…”

Section: A Hypothesis On the Origin Of Mtdna Mutationssupporting

confidence: 86%

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

Matkarimov

Saparbaev

2019

Preprint

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A variety of endogenous and exogenous factors induce chemical and structural alterations to cellular DNA, as well as errors occurring throughout DNA synthesis. These DNA damages are cytotoxic, miscoding, or both, and are believed to be at the origin of cancer and other age related diseases. A human cell, in addition to nuclear DNA, contains thousands copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It was proposed that mtDNA is a critical target for reactive oxygen species (ROS), by-products of the oxidative phosphorylation (OXPHOS), generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA are more extensive and persistent as compared to that of nuclear DNA. Although, transversions are the hallmarks of mutations induced by ROS, paradoxically, the majority of mtDNA mutations that occurred during ageing and cancer are transitions. Furthermore, these mutations exhibit a striking strand orientation bias: T→C/G→A transitions preferentially occur on the Light strand, whereas C→T/A→G on the Heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the Heavy strand only, due to asymmetric replication of the DNA strand anchored to inner membrane via D-loop structure.

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Section: A Hypothesis On the Origin Of Mtdna Mutationssupporting

confidence: 86%

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

Matkarimov

Saparbaev

2019

Preprint

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“…Although mtDNA is much smaller than nDNA, the mechanism of its replication is poorly understood, and ribonucleotides can be present in mtDNA after it completes its replication [68]. Polymerase gamma has a proofreading activity and is supported by the action of PrimPol (primase and DNA-directed polymerase), providing primers for PolG, playing a role in mtDNA damage tolerance, and being required for reinitiation of replication stalled by mtDNA damage [69].…”

Section: Dna Damage Response In Mtdnamentioning

confidence: 99%

Role of Mitochondrial DNA Damage in ROS-Mediated Pathogenesis of Age-Related Macular Degeneration (AMD)

Kaarniranta

Pawłowska

Szczepańska

et al. 2019

IJMS

147

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Age-related macular degeneration (AMD) is a complex eye disease that affects millions of people worldwide and is the main reason for legal blindness and vision loss in the elderly in developed countries. Although the cause of AMD pathogenesis is not known, oxidative stress-related damage to retinal pigment epithelium (RPE) is considered an early event in AMD induction. However, the precise cause of such damage and of the induction of oxidative stress, including related oxidative effects occurring in RPE and the onset and progression of AMD, are not well understood. Many results point to mitochondria as a source of elevated levels of reactive oxygen species (ROS) in AMD. This ROS increase can be associated with aging and effects induced by other AMD risk factors and is correlated with damage to mitochondrial DNA. Therefore, mitochondrial DNA (mtDNA) damage can be an essential element of AMD pathogenesis. This is supported by many studies that show a greater susceptibility of mtDNA than nuclear DNA to DNA-damaging agents in AMD. Therefore, the mitochondrial DNA damage reaction (mtDDR) is important in AMD prevention and in slowing down its progression as is ROS-targeting AMD therapy. However, we know far less about mtDNA than its nuclear counterparts. Further research should measure DNA damage in order to compare it in mitochondria and the nucleus, as current methods have serious disadvantages.

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“…Interestingly, a RecQ helicase, RecQ4, is also found in mitochondria, and other nuclear helicases involved in nuclear DNA repair are present, namely SUV3, DNA2, and PIF1 [119]. Even the replicative mitochondrial helicase TWNK was found to have strand-exchange activity [120] and therefore might be a core component of a mitochondrial recombination machinery [121].…”

Section: Open Questionsmentioning

confidence: 99%

Twist and Turn—Topoisomerase Functions in Mitochondrial DNA Maintenance

Goffart

Hangas

Pohjoismäki

2019

IJMS

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Like any genome, mitochondrial DNA (mtDNA) also requires the action of topoisomerases to resolve topological problems in its maintenance, but for a long time, little was known about mitochondrial topoisomerases. The last years have brought a closer insight into the function of these fascinating enzymes in mtDNA topology regulation, replication, transcription, and segregation. Here, we summarize the current knowledge about mitochondrial topoisomerases, paying special attention to mammalian mitochondrial genome maintenance. We also discuss the open gaps in the existing knowledge of mtDNA topology control and the potential involvement of mitochondrial topoisomerases in human pathologies. While Top1mt, the only exclusively mitochondrial topoisomerase in mammals, has been studied intensively for nearly a decade, only recent studies have shed some light onto the mitochondrial function of Top2β and Top3α, enzymes that are shared between nucleus and mitochondria. Top3α mediates the segregation of freshly replicated mtDNA molecules, and its dysfunction leads to mtDNA aggregation and copy number depletion in patients. Top2β, in contrast, regulates mitochondrial DNA replication and transcription through the alteration of mtDNA topology, a fact that should be acknowledged due to the frequent use of Topoisomerase 2 inhibitors in medical therapy.

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Known Unknowns of Mammalian Mitochondrial DNA Maintenance

Cited by 18 publications

References 99 publications

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

Role of Mitochondrial DNA Damage in ROS-Mediated Pathogenesis of Age-Related Macular Degeneration (AMD)

Twist and Turn—Topoisomerase Functions in Mitochondrial DNA Maintenance

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