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The Emerging Nexus of Active DNA Demethylation and Mitochondrial Oxidative Metabolism in Post-Mitotic Neurons

1
Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China
2
Key Laboratory of Model Animal for Disease Study, Ministry of Education, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2014, 15(12), 22604-22625; https://doi.org/10.3390/ijms151222604
Received: 15 September 2014 / Revised: 12 November 2014 / Accepted: 28 November 2014 / Published: 5 December 2014
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
The variable patterns of DNA methylation in mammals have been linked to a number of physiological processes, including normal embryonic development and disease pathogenesis. Active removal of DNA methylation, which potentially regulates neuronal gene expression both globally and gene specifically, has been recently implicated in neuronal plasticity, learning and memory processes. Model pathways of active DNA demethylation involve ten-eleven translocation (TET) methylcytosine dioxygenases that are dependent on oxidative metabolites. In addition, reactive oxygen species (ROS) and oxidizing agents generate oxidative modifications of DNA bases that can be removed by base excision repair proteins. These potentially link the two processes of active DNA demethylation and mitochondrial oxidative metabolism in post-mitotic neurons. We review the current biochemical understanding of the DNA demethylation process and discuss its potential interaction with oxidative metabolism. We then summarise the emerging roles of both processes and their interaction in neural plasticity and memory formation and the pathophysiology of neurodegeneration. Finally, possible therapeutic approaches for neurodegenerative diseases are proposed, including reprogramming therapy by global DNA demethylation and mitohormesis therapy for locus-specific DNA demethylation in post-mitotic neurons. View Full-Text
Keywords: active DNA demethylation; mitochondrial oxidative metabolism; TET (ten-eleven translocation) methylcytosine dioxygenases; post-mitotic neurons; neurodegeneration active DNA demethylation; mitochondrial oxidative metabolism; TET (ten-eleven translocation) methylcytosine dioxygenases; post-mitotic neurons; neurodegeneration
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Meng, H.; Chen, G.; Gao, H.-M.; Song, X.; Shi, Y.; Cao, L. The Emerging Nexus of Active DNA Demethylation and Mitochondrial Oxidative Metabolism in Post-Mitotic Neurons. Int. J. Mol. Sci. 2014, 15, 22604-22625.

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