DNA Methyltransferase1 (DNMT1) Isoform3 methylates mitochondrial genome and modulates its biology

Saini, Sunil; Mangalhara, Kailash Chandra; Prakasam, Gopinath; Bamezai, R.

doi:10.1038/s41598-017-01743-y

Cited by 73 publications

(52 citation statements)

References 29 publications

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“…In fact, hypomethylation of mtDNA was already suggested as a cause for the increased expression of mtDNA-encoded genes (Yamazaki et al, 2016). More recently, and strengthening our hypothesis, a downregulation in the expression of DNMT1 accompanied by mtDNA hypomethylation was observed under conditions of oxidative stress (Saini et al, 2017). However, it is worth mentioning that our study has some limitations that have been considered for data analyses, one being the failure to confirm mtDNA methylation.…”

Section: Discussionsupporting

confidence: 48%

Single nanomolar doxorubicin exposure triggers compensatory mitochondrial responses in H9c2 cardiomyoblasts

Ferreira

Cunha‐Oliveira

Veloso

et al. 2019

Food and Chemical Toxicology

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A B S T R A C TDose-dependent and cumulative cardiotoxicity associated with doxorubicin (DOX) is the main limitation of anticancer therapy. Pediatric cancer survivors are particularly vulnerable, and no effective prevention measures are available. The aim of the present study was to investigate the persistent effects of nanomolar DOX concentrations and determine whether a pretreatment would induce mitochondrial adaptations in H9c2 cardiomyoblasts. H9c2 cells were incubated with DOX (10 and 25 nM) for 24 h, followed by 9 days of recovery in drugfree medium. We found that the sub-therapeutic DOX treatment induced persistent hypertrophy and dose-dependent cell cycle arrest in G2/M. Glycolytic activity, indirectly based on extracellular acidification rate, and basal respiration were significantly decreased in DOX-treated cells compared to controls, although both groups showed similar maximal respiration. Additionally, nanomolar DOX pretreatment resulted in upregulation of mitochondrial DNA transcripts accompanied by a decrease in DNA methyltransferase 1 (DNMT1) and global methylation levels. Finally, the pretreatment with DOX ameliorated H9c2 cells resistance against a subsequent exposure to DOX. These results suggest that nanomolar DOX pretreatment induced a beneficial and possibly epigenetic-based mitochondrial adaptation, raising the possibility that an early sub-therapeutic DOX treatment can be used as a preconditioning and protective approach during anticancer therapies.

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Section: Discussionsupporting

confidence: 48%

Single nanomolar doxorubicin exposure triggers compensatory mitochondrial responses in H9c2 cardiomyoblasts

Ferreira

Cunha‐Oliveira

Veloso

et al. 2019

Food and Chemical Toxicology

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“…Over the last decade, mtDNA methylation has been extensively scrutinized as several studies have identified this modification in cell lines and tissue samples of mouse and human origin, in both normal as well as disease conditions, in young versus aged mice, as well as under various conditions of oxidative stress, nutrition, and environmental exposure (Chestnut et al, 2011;Shock et al, 2011;Dzitoyeva et al, 2012;Bellizzi et al, 2013;Pirola et al, 2013;Wong et al, 2013;Ghosh et al, 2014;Baccarelli and Byun, 2015;Saini et al, 2017). Over the last decade, mtDNA methylation has been extensively scrutinized as several studies have identified this modification in cell lines and tissue samples of mouse and human origin, in both normal as well as disease conditions, in young versus aged mice, as well as under various conditions of oxidative stress, nutrition, and environmental exposure (Chestnut et al, 2011;Shock et al, 2011;Dzitoyeva et al, 2012;Bellizzi et al, 2013;Pirola et al, 2013;Wong et al, 2013;Ghosh et al, 2014;Baccarelli and Byun, 2015;Saini et al, 2017).…”

Section: The Enigma Of Mtdna Methylationmentioning

confidence: 99%

“…The mechanism of DNA methylation and demethylation in the mitochondria is still not clearly understood. Over the last decade, mtDNA methylation has been extensively scrutinized as several studies have identified this modification in cell lines and tissue samples of mouse and human origin, in both normal as well as disease conditions, in young versus aged mice, as well as under various conditions of oxidative stress, nutrition, and environmental exposure (Chestnut et al, 2011;Shock et al, 2011;Dzitoyeva et al, 2012;Bellizzi et al, 2013;Pirola et al, 2013;Wong et al, 2013;Ghosh et al, 2014;Baccarelli and Byun, 2015;Saini et al, 2017). Controversial reports observe either the presence or complete absence of mtDNA methylation in the noncoding control region within a short 7S DNA fragment that results in a three-stranded displacement or D-loop structure, as well as within several rRNA, tRNA, and protein encoding genes (Hong et al, 2013;Wong et al, 2013;Ghosh et al, 2014;Liu et al, 2016;Mechta et al, 2017;Mposhi et al, 2017;Matsuda et al, 2018;Owa et al, 2018).…”

Section: The Enigma Of Mtdna Methylationmentioning

confidence: 99%

“…The earliest evidence of DNMT activity in mitochondria was observed in vertebrates including loach embryos, rat liver, ox, as well as in mouse and hamster cells (Vanyushin et al, 1971;Vanyushin and Kirnos, 1976;Vanyushin and Kirnos, 1977). The expression of various DNMTs in different cell types is also controversial and appears to be preferential depending upon the cell and tissue type being studied (Saini et al, 2017;reviewed in Maresca et al, 2015). Currently, DNMT1, DNMT3a, DNMT3b, and two TET enzymes (TET1 and TET2) have been identified within the mitochondria using immunofluorescence and western blotting procedures (Chestnut et al, 2011;Shock et al, 2011;Chen et al, 2012;Dzitoyeva et al, 2012;Bellizzi et al, 2013;Wong et al, 2013;reviewed in Maresca et al, 2015).…”

Section: The Enigma Of Mtdna Methylationmentioning

confidence: 99%

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Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

128

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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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“…However, the presence of this epigenetic modification in mitochondrion has been challenged due to conflicting findings 13,14 . Intriguingly, several studies showed the presence of DNA methyltransferases (DNMTs), mainly DNMT1 and DNMT3A, inside mitochondria in support of the occurrence of methylation [15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Hypermethylation of mitochondrial DNA in vascular smooth muscle cells impairs cell contractility

et al. 2020

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Vascular smooth muscle cell (SMC) from arterial stenotic-occlusive diseases is featured with deficiency in mitochondrial respiration and loss of cell contractility. However, the regulatory mechanism of mitochondrial genes and mitochondrial energy metabolism in SMC remains elusive. Here, we described that DNA methyltransferase 1 (DNMT1) translocated to the mitochondria and catalyzed D-loop methylation of mitochondrial DNA in vascular SMCs in response to platelet-derived growth factor-BB (PDGF-BB). Mitochondrial-specific expression of DNMT1 repressed mitochondrial gene expression, caused functional damage, and reduced SMC contractility. Hypermethylation of mitochondrial D-loop regions were detected in the intima-media layer of mouse carotid arteries subjected to either cessation of blood flow or mechanical endothelial injury, and also in vessel specimens from patients with carotid occlusive diseases. Likewise, the ligated mouse arteries exhibited an enhanced mitochondrial binding of DNMT1, repressed mitochondrial gene expression, defects in mitochondrial respiration, and impaired contractility. The impaired contractility of a ligated vessel could be restored by ex vivo transplantation of DNMT1-deleted mitochondria. In summary, we discovered the function of DNMT1-mediated mitochondrial D-loop methylation in the regulation of mitochondrial gene transcription. Methylation of mitochondrial D-loop in vascular SMCs contributes to impaired mitochondrial function and loss of contractile phenotype in vascular occlusive disease.

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DNA Methyltransferase1 (DNMT1) Isoform3 methylates mitochondrial genome and modulates its biology

Cited by 73 publications

References 29 publications

Single nanomolar doxorubicin exposure triggers compensatory mitochondrial responses in H9c2 cardiomyoblasts

Single nanomolar doxorubicin exposure triggers compensatory mitochondrial responses in H9c2 cardiomyoblasts

Mitochondrial DNA: Epigenetics and environment

Hypermethylation of mitochondrial DNA in vascular smooth muscle cells impairs cell contractility

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