Hypomethylation of mitochondrial D-loop and ND6 with increased mitochondrial DNA copy number in the arsenic-exposed population

Sanyal, Tamalika; Bhattacharjee, Pritha; Bhattacharjee, Sandip

doi:10.1016/j.tox.2018.06.012

Cited by 53 publications

(38 citation statements)

References 46 publications

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“…DOI 10.1002/em genes was observed following chromium exposure in chrome plating workers (Yang et al, 2016). Likewise, arsenic exposure was associated with hypomethylation of the D-loop and MT-ND6 in an Indian population exposed to high concentration of arsenic present in drinking water (Sanyal et al, 2018). Furthermore, arsenic exposure also resulted in an increase in mtDNA copy number, upregulation in the expression of the nuclear-encoded TFAM gene, and increased expression of the mitochondrial proteins ND4 and ND6 (Sanyal et al, 2018).…”

Section: Impact Of Xenobiotics On Mtdna Methylationmentioning

confidence: 97%

“…Likewise, arsenic exposure was associated with hypomethylation of the D-loop and MT-ND6 in an Indian population exposed to high concentration of arsenic present in drinking water (Sanyal et al, 2018). Furthermore, arsenic exposure also resulted in an increase in mtDNA copy number, upregulation in the expression of the nuclear-encoded TFAM gene, and increased expression of the mitochondrial proteins ND4 and ND6 (Sanyal et al, 2018). Another environmental agent used in building materials, electronics, furniture, vehicles, and plastics known as polybrominated diphenyl ethers (PBDEs) are flame retardant substances that can cause neurological impairment.…”

Section: Impact Of Xenobiotics On Mtdna Methylationmentioning

confidence: 98%

“…Hypomethylation in the MT-TF and MT-RMR1 Environmental and Molecular Mutagenesis. Furthermore, arsenic exposure also resulted in an increase in mtDNA copy number, upregulation in the expression of the nuclear-encoded TFAM gene, and increased expression of the mitochondrial proteins ND4 and ND6 (Sanyal et al, 2018). Likewise, arsenic exposure was associated with hypomethylation of the D-loop and MT-ND6 in an Indian population exposed to high concentration of arsenic present in drinking water (Sanyal et al, 2018).…”

Section: Impact Of Xenobiotics On Mtdna Methylationmentioning

confidence: 98%

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Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

107

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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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Section: Impact Of Xenobiotics On Mtdna Methylationmentioning

confidence: 97%

Section: Impact Of Xenobiotics On Mtdna Methylationmentioning

confidence: 98%

Section: Impact Of Xenobiotics On Mtdna Methylationmentioning

confidence: 98%

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Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

107

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“…DNMT3A was also found in mitochondria of skeletal muscle and central nervous system from adult mouse or human 17 . Although contradictory reports also revealed an absence of CpG methylation in mitochondria, which might be due to different experimental conditions 12 , evidence favoring methylation of mtDNA methylation continued to emerge 30,31 . Here, we demonstrated not only the presence of DNMT1 and 5-methylcytosine in mtDNA, but also the translocation of DNMT1 from the nuclei to the mitochondria in response to PDGF-BB in vascular SMCs (Fig.…”

Section: Discussionmentioning

confidence: 91%

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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“…The LPS promoter is an important component of the non-coding region contributing to the expression of the OXPHOS complex I subunit ND6 [21]. The methylation of the ND6 gene was reported in many studies [24,34,35]. For instance, Pirola et al [24] analysed the methylation of ND6, COX1, and the D-loop region with the use of quantitative methylation specific-PCR in the context of non-alcoholic fatty liver disease in humans [24].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of CpG Sites and Islands Distributed in Mitochondrial DNA of Model Organisms

Kowal

Tkaczyk

Ząbek

et al. 2020

Animals

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The information about mtDNA methylation is still limited, thus epigenetic modification remains unclear. The lack of comprehensive information on the comparative epigenomics of mtDNA prompts comprehensive investigations of the epigenomic modification of mtDNA in different species. This is the first study in which the theoretical CpG localization in the mtDNA reference sequences from various species (12) was compared. The aim of the study was to determine the localization of CpG sites and islands in mtDNA of model organisms and to compare their distribution. The results are suitable for further investigations of mtDNA methylation. The analysis involved both strands of mtDNA sequences of animal model organisms representing different taxonomic groups of invertebrates and vertebrates. For each sequence, such parameters as the number, length, and localization of CpG islands were determined with the use of EMBOSS (European Molecular Biology Open Software Suite) software. The number of CpG sites for each sequence was indicated using the newcpgseek algorithm. The results showed that methylation of mtDNA in the analysed species involved mitochondrial gene expression. Our analyses showed that the CpG sites were commonly present in genomic regions including the D-loop, CYTB, ND6, ND5, ND4, ND3, ND2, ND1, COX3, COX2, COX1, ATP6, 16s rRNA, and 12s rRNA. The CpG distribution in animals from different species was diversified. Generally, the number of observed CpG sites of the mitochondrial genome was higher in the vertebrates than in the invertebrates. However, there was no relationship between the frequency of the CpG sites in the mitochondrial genome and the complexity of the analysed organisms. Interestingly, the distribution of the CpG sites for tRNA coding genes was usually cumulated in a larger CpG region in vertebrates. This paper may be a starting point for further research, since the collected information indicates possible methylation regions localized in mtDNA among different species including invertebrates and vertebrates.

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Hypomethylation of mitochondrial D-loop and ND6 with increased mitochondrial DNA copy number in the arsenic-exposed population

Cited by 53 publications

References 46 publications

Mitochondrial DNA: Epigenetics and environment

Mitochondrial DNA: Epigenetics and environment

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

Comparative Analysis of CpG Sites and Islands Distributed in Mitochondrial DNA of Model Organisms

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