Dna Methyltransferase 1 Mutations and Mitochondrial Pathology: Is Mtdna Methylated?

Abstract

Autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E) are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine-5)-methyltransferase 1 (DNMT1). DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy, and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA) suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however, mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is regulated and executed?

Mitochondrial DNA: Epigenetics and environment

“…DNA methylation is the addition of a methyl group from S-adenosyl-methionine (SAM) to a DNA base usually cytosine (C) or adenine (A) that is catalyzed by specialized enzymes called DNA methyltransferases (DNMTs; reviewed in Maresca et al, 2015). Although cytosine methylation occurs at position C-5 resulting in 5-methylcytosine (5mC), the exocyclic NH 2 group of adenine gets methylated at position 6, which is converted into N6-methyladenine (6mA; Figs.…”

“…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). DNA methylation in the mitochondria was first reported almost five decades ago and has been a topic of controversy ever since (reviewed in Maresca et al, 2015;D'Aquila et al, 2017;Mposhi et al, 2017). It is advantageous to measure methylation within the mitochondrial D-loop, because this region harbors the HSP and LSP elements and is easily accessible to proteins during mtDNA replication and transcription where methylation can directly impact these processes .…”

“…It is advantageous to measure methylation within the mitochondrial D-loop, because this region harbors the HSP and LSP elements and is easily accessible to proteins during mtDNA replication and transcription where methylation can directly impact these processes . DNA methylation in the mitochondria was first reported almost five decades ago and has been a topic of controversy ever since (reviewed in Maresca et al, 2015;D'Aquila et al, 2017;Mposhi et al, 2017). In earlier studies in the 1970s, the presence of 5mC was reported in mouse and hamster cell lines (Nass, 1973), as well as in bovine and rat liver mtDNA (Kirnos and Vaniushin, 1976).…”

DNMT1 modulation in chronic hepatitis B patients and hypothetic influence on mitochondrial DNA methylation status during long‐term nucleo(t)side analogs therapy

“…Among these, there are increasing indication that certain chemicals substances and drugs may regulate gene expression not only during but also after exposure . Epigenetic modification of the mitochondrial genome has been widely debated, but the most recently published data highlight how the methylation of cytosines in the mitochondrial DNA is likely to be much more frequent than previously believed . Particularly relevant is the binding of DNMT1 to the mitochondrial D‐loop control region, the latter driving transcription initiation of both heavy and light strands and playing a role in the regulation of mitochondrial gene expression …”

A novel mutation in the DNMT1 gene in a patient presenting with pure cerebellar ataxia

“…DNA methylation is a key process for gene expression owing to its effect on DNA replication and repair [5] (Fig. 2).…”