Mitochondrial DNA replication in mammalian cells: overview of the pathway

Falkenberg, Maria

doi:10.1042/ebc20170100

Cited by 134 publications

(117 citation statements)

References 93 publications

(94 reference statements)

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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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“…1; reviewed in Young and Copeland, 2016;Falkenberg, 2018). 1; reviewed in Young and Copeland, 2016;Falkenberg, 2018).…”

Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

“…1; reviewed in Young and Copeland, 2016;Falkenberg, 2018). The three main players involved with the process of mtDNA replication are DNA polymerase gamma (Polγ), the mitochondrial helicase, TWINKLE, and the mitochondrial single-stranded DNAbinding protein (mtSSB; Lee et al, 2009;reviewed in Graziewicz et al, 2006;Falkenberg, 2018;Yasukawa and Kang, 2018). The three main players involved with the process of mtDNA replication are DNA polymerase gamma (Polγ), the mitochondrial helicase, TWINKLE, and the mitochondrial single-stranded DNAbinding protein (mtSSB; Lee et al, 2009;reviewed in Graziewicz et al, 2006;Falkenberg, 2018;Yasukawa and Kang, 2018).…”

Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

“…The NCR within mtDNA harbors an origin of replication on the heavy strand (O H ) as well as a second origin on the light strand (O L ), which is located approximately 11 kb away from O H (Fig. 1; reviewed in Young and Copeland, 2016;Falkenberg, 2018). The exact mechanism of mitochondrial replication is unknown and there are conflicting theories about the process (reviewed in Falkenberg, 2018;Yasukawa and Kang, 2018).…”

Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

“…The exact mechanism of mitochondrial replication is unknown and there are conflicting theories about the process (reviewed in Falkenberg, 2018;Yasukawa and Kang, 2018). The three main players involved with the process of mtDNA replication are DNA polymerase gamma (Polγ), the mitochondrial helicase, TWINKLE, and the mitochondrial single-stranded DNAbinding protein (mtSSB; Lee et al, 2009;reviewed in Graziewicz et al, 2006;Falkenberg, 2018;Yasukawa and Kang, 2018). The Polγ holoenzyme is a heterotrimer consisting of two identical accessory subunits (Polγ-B) and one catalytic subunit (Polγ-A), where the accessory subunits enhance the processivity and catalytic function of Polγ-A (Gray and Wong, 1992;Johnson et al, 2000;Carrodeguas et al, 2002;reviewed in Kaguni, 2004).…”

Section: Mtdna Replicationtranscription and Repairmentioning

confidence: 99%

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Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

122

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Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. Although only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post‐translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging‐related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short noncoding RNAs, and post‐translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. Environ. Mol. Mutagen., 60:668–682, 2019. © 2019 Wiley Periodicals, Inc.

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Mitochondrial DNA copy number in human disease: the more the better?

et al. 2020

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Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene-dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.

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Mitochondrial DNA replication in mammalian cells: overview of the pathway

Cited by 134 publications

References 93 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

Mitochondrial DNA: Epigenetics and environment

Mitochondrial DNA copy number in human disease: the more the better?

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