Mitochondrial DNA Copy Number and D-Loop Region Methylation in Carriers of Amyotrophic Lateral Sclerosis Gene Mutations

Stoccoro, Andrea; Mosca, Lorena; Carnicelli, Vittoria; Cavallari, Ugo; Lunetta, Christian; Marocchi, Alessandro; Migliore, Lucia; Coppedè, Fabio

doi:10.2217/epi-2018-0072

Cited by 56 publications

(69 citation statements)

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“…Present data also confirm our previous investigation in familial ALS, revealing that among carriers of the major ALS-causative genes, namely SOD1, C9orf72, FUS, and TARDBP, D-loop methylation levels were significantly reduced only in SOD1 carriers [23]. Collectively, these studies suggest that each ALScausative gene contributes to nuclear and mitochondrial DNA methylation alteration in a different manner [14,23,26]. Furthermore, it has been reported that ALS-causative genes are able to interact with epigenetic writer and reader proteins [12].…”

Section: Discussionsupporting

confidence: 92%

“…Accumulating evidence suggests impaired mtDNA methylation in patients with neurodegenerative diseases, and particularly in the regulatory D-loop region [19][20][21][22][23]. Indeed, altered D-loop methylation levels have been observed in cortical regions of AD patients and transgenic AD mice [19,21], in the substantia nigra of PD patients [19], and in the peripheral blood cells of sporadic AD patients [20].…”

Section: Discussionmentioning

confidence: 99%

“…Given that the mitochondria play fundamental roles in numerous cellular functions, and that their alterations are involved in several pathologies, numerous authors searched for altered mtDNA methylation in human diseases, and increasing evidence suggests that an increase in mtDNA copy number and mitochondrial transcription, resulting from mtDNA methylation changes, might be a compensatory mechanism to counteract oxidative stress and/or an increased ATP demand under conditions of oxidative stress and metabolic dysfunctions such as those resulting from placental insufficiency [46], cancer [38], obesity, and diabetes [37]. Indeed, we previously suggested that the reduced D-loop methylation levels leading to an increased mtDNA copy number in carriers of ALS-linked SOD1 mutations could represent a compensatory mechanism to counteract the increased oxidative stress, impaired mitochondrial respiration, and increased mtDNA damage in those subjects [23]. In this regard, it has also been recently demonstrated that DNA repair genes are hypomethylated and overexpressed to counteract oxidative DNA damage in human ALS motor neurons with SOD1 mutations [47].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we recently investigated ALS families with SOD1, C9orf72, FUS, or TARDBP pathogenetic variants, observing that the methylation levels of the mitochondrial D-loop region were significantly decreased only in peripheral blood lymphocytes of carriers of ALS-linked SOD1 variants, either ALS patients or pre-symptomatic carriers. Moreover, D-loop methylation levels resulted inversely correlated with the mtDNA copy number, suggesting that among familial ALS cases, changes in mitochondrial epigenetics leading to increased mtDNA replication could be particularly relevant for those with an impaired antioxidant defense, due to the presence of SOD1 mutations [23]. However, nothing is still known concerning the mitochondrial epigenetics of sporadic ALS cases, which represent the vast majority of ALS patients.…”

Section: Introductionmentioning

confidence: 99%

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Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

et al. 2020

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Background Mitochondrial dysregulation and aberrant epigenetic mechanisms have been frequently reported in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and several researchers suggested that epigenetic dysregulation in mitochondrial DNA (mtDNA) could contribute to the neurodegenerative process. We recently screened families with mutations in the major ALS causative genes, namely C9orf72, SOD1, FUS, and TARDBP, observing reduced methylation levels of the mtDNA regulatory region (D-loop) only in peripheral lymphocytes of SOD1 carriers. However, until now no studies investigated the potential role of mtDNA methylation impairment in the sporadic form of ALS, which accounts for the majority of disease cases. The aim of the current study was to investigate the D-loop methylation levels and the mtDNA copy number in sporadic ALS patients and compare them to those observed in healthy controls and in familial ALS patients. Pyrosequencing analysis of D-loop methylation levels and quantitative analysis of mtDNA copy number were performed in peripheral white blood cells from 36 sporadic ALS patients, 51 age- and sex-matched controls, and 27 familial ALS patients with germinal mutations in SOD1 or C9orf72 that represent the major familial ALS forms. Results In the total sample, D-loop methylation levels were significantly lower in ALS patients compared to controls, and a significant inverse correlation between D-loop methylation levels and the mtDNA copy number was observed. Stratification of ALS patients into different subtypes revealed that both SOD1-mutant and sporadic ALS patients showed lower D-loop methylation levels compared to controls, while C9orf72-ALS patients showed similar D-loop methylation levels than controls. In healthy controls, but not in ALS patients, D-loop methylation levels decreased with increasing age at sampling and were higher in males compared to females. Conclusions Present data reveal altered D-loop methylation levels in sporadic ALS and confirm previous evidence of an inverse correlation between D-loop methylation levels and the mtDNA copy number, as well as differences among the major familial ALS subtypes. Overall, present results suggest that D-loop methylation and mitochondrial replication are strictly related to each other and could represent compensatory mechanisms to counteract mitochondrial impairment in sporadic and SOD1-related ALS forms.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

et al. 2020

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“…Indeed, the D-loop locus implicated in the processing of the RNA primer for mitochondrial replication was found to be methylated in human and murine peripheral blood [33,39], suggesting a role for mtDNA methylation in the control of mtDNA replication [40]. Indeed, D-loop methylation alterations have been associated with numerous pathological conditions, ranging from cancer to CVD, neurodegeneration, and others [36,39,[41][42][43][44].…”

Section: Mitochondrial Dna: From Genetics To Epigeneticsmentioning

confidence: 99%

Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?

Bordoni

Gabbianelli

2020

Antioxidants

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The maintenance of the mitochondrial function is essential in preventing and counteracting neurodegeneration. In particular, mitochondria of neuronal cells play a pivotal role in sustaining the high energetic metabolism of these cells and are especially prone to oxidative damage. Since overproduction of reactive oxygen species (ROS) is involved in the pathogenesis of neurodegeneration, dietary antioxidants have been suggested to counteract the detrimental effects of ROS and to preserve the mitochondrial function, thus slowing the progression and limiting the extent of neuronal cell loss in neurodegenerative disorders. In addition to their role in the redox-system homeostasis, mitochondria are unique organelles in that they contain their own genome (mtDNA), which acts at the interface between environmental exposures and the molecular triggers of neurodegeneration. Indeed, it has been demonstrated that mtDNA (including both genetics and, from recent evidence, epigenetics) might play relevant roles in modulating the risk for neurodegenerative disorders. This mini-review describes the link between the mitochondrial genome and cellular oxidative status, with a particular focus on neurodegeneration; moreover, it provides an overview on potential beneficial effects of antioxidants in preserving mitochondrial functions through the protection of mtDNA.

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Susceptibility Genes and Epigenetics in Sporadic ALS

Morrice

Shaw

Gregory‐Evans

2021

Spectrums of Amyotrophic Lateral Sclerosis

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Mitochondrial DNA Copy Number and D-Loop Region Methylation in Carriers of Amyotrophic Lateral Sclerosis Gene Mutations

Abstract: Demethylation of the D-loop region could represent a compensatory mechanism for mtDNA upregulation in carriers of ALS-linked SOD1 mutations.

Cited by 56 publications

References 57 publications

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

Reduced mitochondrial D-loop methylation levels in sporadic amyotrophic lateral sclerosis

Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?

Susceptibility Genes and Epigenetics in Sporadic ALS

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