ArticleHuman molecular genetics2020
DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
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- Disease-Associated Mutations Impact DNA Methyltransferase 1 Function through Dynamic Allosteric Effects and Solvent Exposure.Journal of chemical theory and computation · 2026Article
- TDP-43 controls RNA structure through high affinity lattice interactions.Nature communications · 2026Article
- Association between the oxidative balance score and biological aging measured by epigenetic clock: insight from the NHANES 1999-2002.Clinical epigenetics · 2026Article
- TDP-43 controls RNA structure through high affinity lattice interactions.bioRxiv : the preprint server for biology · 2025Article
- Mitochondrial DNA signals driving immune responses: Why, How, Where?Cell communication and signaling : CCS · 2025Review
- Synergistic Neuroprotection Through Epigenetic Modulation by Combined Curcumin-Enriched Turmeric Extract and L-Ascorbic Acid in Oxidative Stress-Induced SH-SY5Y Cell Damage.Foods (Basel, Switzerland) · 2025Article
- Elevated circulating cell-free mitochondrial DNA level in cerebrospinal fluid of narcolepsy type 1.Brain communications · 2025Article
- Cytosine methylase and hydroxymethylase activity in mammalian mitochondria.Frontiers in cell and developmental biology · 2025Article
- Mechanisms of DNA Methylation Regulatory Function and Crosstalk with Histone Lysine Methylation.Journal of molecular biology · 2024Review
- Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment.Human molecular genetics · 2023Article
- Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-ketoglutarate.Blood advances · 2023Article
- Psychostimulants influence oxidative stress and redox signatures: the role of DNA methylation.Redox report : communications in free radical research · 2022Review
- Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNAMolecular medicine (Cambridge, Mass.) · 2022Article
- Ultra-deep whole genome bisulfite sequencing reveals a single methylation hotspot in human brain mitochondrial DNA.Epigenetics · 2022Article
- Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve.Biomolecules · 2021Review
- A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies.Human molecular genetics · 2021Article
- Insights on Targeting Small Molecules to the Mitochondrial Matrix and the Preparation of MitoB and MitoP as Exomarkers of Mitochondrial Hydrogen Peroxide.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?Antioxidants (Basel, Switzerland) · 2020Review
- DNMT1 as an environmental sensor: epigenetic pathways linking environmental exposures, sex hormone signaling, and vulnerability to neurodevelopmental and neurodegenerative diseases.Frontiers in neurologyReview
Corrections and comments
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Authors and funding
26 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ADCA-DN and HSN-IE are rare neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence (RFTS) of the DNA methyltransferase 1 (DNMT1) gene. Both phenotypes resemble mitochondrial disorders, and mitochondrial dysfunction was first observed in ADCA-DN. To explore mitochondrial involvement, we studied the effects of DNMT1 mutations in fibroblasts from four ADCA-DN and two HSN-IE patients. We documented impaired activity of purified DNMT1 mutant proteins, which in fibroblasts results in increased DNMT1 amount. We demonstrated that DNMT1 is not localized within mitochondria, but it is associated with the mitochondrial outer membrane. Concordantly, mitochondrial DNA failed to show meaningful CpG methylation. Strikingly, we found activated mitobiogenesis and OXPHOS with significant increase of H2O2, sharply contrasting with a reduced ATP content. Metabolomics profiling of mutant cells highlighted purine, arginine/urea cycle and glutamate metabolisms as the most consistently altered pathways, similar to primary mitochondrial diseases. The most severe mutations showed activation of energy shortage AMPK-dependent sensing, leading to mTORC1 inhibition. We propose that DNMT1 RFTS mutations deregulate metabolism lowering ATP levels, as a result of increased purine catabolism and urea cycle pathways. This is associated with a paradoxical mitochondrial hyper-function and increased oxidative stress, possibly resulting in neurodegeneration in non-dividing cells.
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