title: The emerging nexus of active DNA demethylation and mitochondrial oxidative metabolism in post-mitotic neurons.
abstract: 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.
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China. menghuan@mail.cmu.edu.cn.
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.affiliation: Key Laboratory of Model Animal for Disease Study, Ministry of Education, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China. chengq@nicemice.cn.
authors.forename: Guiquan
authors.initials: G
authors.lastname: Chen
authors.affiliation: Key Laboratory of Model Animal for Disease Study, Ministry of Education, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China. gaohm@nicemice.cn.
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Gao
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China. xysong@mail.cmu.edu.cn.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Song
authors.affiliation: Key Laboratory of Model Animal for Disease Study, Ministry of Education, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China. shiyun@nicemice.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China. caoliu@mail.cmu.edu.cn.
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
mesh_terms: D000818:Animals; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D049308:Dioxygenases / Q000378:metabolism; D006801:Humans; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D019279:Resin Cements
chemical_list: C433206:Nexus; D016877:Oxidants; D017382:Reactive Oxygen Species; D019279:Resin Cements; D003596:Cytosine; D049308:Dioxygenases