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Special Issue "Regulation and Biological Role of Mitochondrial DNA Architecture and Topology"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editor

Prof. Dr. Fritz Boege
E-Mail Website
Guest Editor
Institut für Klinische Chemie und Laboratoriumsdiagnostik Universitätsklinikum Düsseldorf (UKD), Moorenstraße 5, Geb. 13.51 (MNR-Klinik), D-40225 Düsseldorf, Germany
Interests: mitochondria; mtDNA maintenance; DNA-topology; DNA-topoisomerases; DNA maintenance; chromatin structure; adrenergic receptors; chronic heart failure; GPCR-autoantibodies; aging; laser-accelerated protons; biomarkers for kidney function and kidney damage

Special Issue Information

Dear Colleagues,

Nearly 20 years ago, it was discovered1,2 that vertebrates have genetically-conserved enzymes dedicated to modifying and controlling mtDNA topology, which indicates that DNA topology and architecture must play a crucial role in mitochondrial function. The above finding raised many questions—to name just a few: How is mtDNA-topology regulated, how does mtDNA replication and transcription impact on mtDNA-topology and vice versa; what role plays DNA topology in mitochondrial stability and mtDNA maintenance; to what extent is regulation of mtDNA topology relevant for mitochondria-delimited etiologies and aging? Meanwhile, a great deal of data germane to these issues have been gathered, and it seems that we are finally approaching a point where clarity emerges from chaos. This Special Issue aims at taking stock of the accumulated knowledge and making an effort to draw a coherent picture of our current understanding of the issue.

1 Zhang, H. et al. Human mitochondrial topoisomerase I. Proc Natl Acad Sci U S A 98, 10608-10613 (2001).

2 Wang, Y., Lyu, Y. L. & Wang, J. C. Dual localization of human DNA topoisomerase IIIalpha to mitochondria and nucleus. Proc Natl Acad Sci U S A 99, 12114-12119 (2002)

Prof. Dr. Fritz Boege
Guest Editor

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Keywords

  • mitochondrial DNA-topoisomerases
  • mtDNA transcription
  • mtDNA replication
  • mtDNA maintenance
  • mtDNA structure
  • mtDNA topology
  • mitochondrial ageing
  • mitochondrial diseases

Published Papers (4 papers)

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Review

Review
Functional Interplay between Cristae Biogenesis, Mitochondrial Dynamics and Mitochondrial DNA Integrity
Int. J. Mol. Sci. 2019, 20(17), 4311; https://doi.org/10.3390/ijms20174311 - 03 Sep 2019
Cited by 32 | Viewed by 3563
Abstract
Mitochondria are vital cellular organelles involved in a plethora of cellular processes such as energy conversion, calcium homeostasis, heme biogenesis, regulation of apoptosis and ROS reactive oxygen species (ROS) production. Although they are frequently depicted as static bean-shaped structures, our view has markedly [...] Read more.
Mitochondria are vital cellular organelles involved in a plethora of cellular processes such as energy conversion, calcium homeostasis, heme biogenesis, regulation of apoptosis and ROS reactive oxygen species (ROS) production. Although they are frequently depicted as static bean-shaped structures, our view has markedly changed over the past few decades as many studies have revealed a remarkable dynamicity of mitochondrial shapes and sizes both at the cellular and intra-mitochondrial levels. Aberrant changes in mitochondrial dynamics and cristae structure are associated with ageing and numerous human diseases (e.g., cancer, diabetes, various neurodegenerative diseases, types of neuro- and myopathies). Another unique feature of mitochondria is that they harbor their own genome, the mitochondrial DNA (mtDNA). MtDNA exists in several hundreds to thousands of copies per cell and is arranged and packaged in the mitochondrial matrix in structures termed mt-nucleoids. Many human diseases are mechanistically linked to mitochondrial dysfunction and alteration of the number and/or the integrity of mtDNA. In particular, several recent studies identified remarkable and partly unexpected links between mitochondrial structure, fusion and fission dynamics, and mtDNA. In this review, we will provide an overview about these recent insights and aim to clarify how mitochondrial dynamics, cristae ultrastructure and mtDNA structure influence each other and determine mitochondrial functions. Full article
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Review
Mammalian Tyrosyl-DNA Phosphodiesterases in the Context of Mitochondrial DNA Repair
Int. J. Mol. Sci. 2019, 20(12), 3015; https://doi.org/10.3390/ijms20123015 - 20 Jun 2019
Cited by 3 | Viewed by 1416
Abstract
Mammalian mitochondria contain four topoisomerases encoded in the nuclear genome: TOP1MT, TOP2α, TOP2β, and TOP3α. They also contain the two known tyrosyl-DNA phosphodiesterases (TDPs): TDP1 and TDP2, including a specific TDP2S isoform. Both TDP1 and TDP2 excise abortive topoisomerase cleavage complexes (TOPccs), [...] Read more.
Mammalian mitochondria contain four topoisomerases encoded in the nuclear genome: TOP1MT, TOP2α, TOP2β, and TOP3α. They also contain the two known tyrosyl-DNA phosphodiesterases (TDPs): TDP1 and TDP2, including a specific TDP2S isoform. Both TDP1 and TDP2 excise abortive topoisomerase cleavage complexes (TOPccs), yet their molecular structures and mechanisms are different. TDP1 is present across eukaryotes, from yeasts to humans and belongs to the phospholipase D family. It functions without a metal cofactor and has a broad activity range, as it also serves to cleanse blocking 3′-DNA ends bearing phosphoglycolate, deoxyribose phosphate, nucleoside, nucleoside analogs (zidovudine), abasic moieties, and with a lower efficiency, TOP2ccs. Found in higher vertebrates, TDP2 is absent in yeast where TDP1 appears to perform its functions. TDP2 belongs to the exonuclease/endonuclease/phosphodiesterase family and requires magnesium as a cofactor to excise TOP2ccs, and it also excises TOP1ccs, albeit with a lower efficiency. Here, we review TDP1 and TDP2 in the context of mitochondrial DNA repair and discuss potential new research areas centered on the mitochondrial TDPs. Full article
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Review
Organization of DNA in Mammalian Mitochondria
Int. J. Mol. Sci. 2019, 20(11), 2770; https://doi.org/10.3390/ijms20112770 - 05 Jun 2019
Cited by 33 | Viewed by 3097
Abstract
As with all organisms that must organize and condense their DNA to fit within the limited volume of a cell or a nucleus, mammalian mitochondrial DNA (mtDNA) is packaged into nucleoprotein structures called nucleoids. In this study, we first introduce the general modes [...] Read more.
As with all organisms that must organize and condense their DNA to fit within the limited volume of a cell or a nucleus, mammalian mitochondrial DNA (mtDNA) is packaged into nucleoprotein structures called nucleoids. In this study, we first introduce the general modes of DNA compaction, especially the role of the nucleoid-associated proteins (NAPs) that structure the bacterial chromosome. We then present the mitochondrial nucleoid and the main factors responsible for packaging of mtDNA: ARS- (autonomously replicating sequence-) binding factor 2 protein (Abf2p) in yeast and mitochondrial transcription factor A (TFAM) in mammals. We summarize the single-molecule manipulation experiments on mtDNA compaction and visualization of mitochondrial nucleoids that have led to our current knowledge on mtDNA compaction. Lastly, we discuss the possible regulatory role of DNA packaging by TFAM in DNA transactions such as mtDNA replication and transcription. Full article
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Review
Twist and Turn—Topoisomerase Functions in Mitochondrial DNA Maintenance
Int. J. Mol. Sci. 2019, 20(8), 2041; https://doi.org/10.3390/ijms20082041 - 25 Apr 2019
Cited by 11 | Viewed by 2724
Abstract
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 [...] Read more.
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. Full article
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