Abstract
Neuroepigenetics, which includes nuclear DNA modifications such as 5-methylcytosine and 5-hydoxymethylcytosine and modifications of nuclear proteins such as histones, is emerging as the leading field in molecular neuroscience. Historically, a functional role for epigenetic mechanisms, including in neuroepigenetics, has been sought in the area of the regulation of nuclear transcription. However, one important compartment of mammalian cell DNA, different from nuclear but equally important for physiological and pathological processes (including in the brain), mitochondrial DNA has for the most part not had a systematic epigenetic characterization. The importance of mitochondria and mitochondrial DNA (particularly its mutations) in central nervous system physiology and pathology has long been recognized. Only recently have mechanisms of mitochondrial DNA methylation and hydroxymethylation, including the discovery of mitochondrial DNA-methyltransferases and the presence and the functionality of 5-methylcytosine and 5-hydroxymethylcytosine in mitochondrial DNA (e.g., in modifying the transcription of mitochondrial genome), been unequivocally recognized as a part of mammalian mitochondrial physiology. Here we summarize for the first time evidence supporting the existence of these mechanisms and we propose the term "mitochondrial epigenetics" to be used when referring to them. Currently, neuroepigenetics does not include mitochondrial epigenetics - a gap that we expect to close in the near future.
Highlights
The earliest understanding of the functional role of epigenetic mechanisms relates to developmental genome regulation; e.g., silencing of gene expression involved in cell differentiation and in maintaining cell phenotypes during cell proliferation [1,2,3,4,5,6]
A structure composed of nuclear DNA and nuclear proteins, has been the primary target of epigenetic research, which brought about major new concepts on the functionality of the genome [7]
Whereas a role for mitochondria and mitochondrially-modulated SAM levels has been explored with respect to ncDNA methylation, no data are available on the role of mitochondria and endogenous SAM modifications in the regulation of mitochondrial DNA (mtDNA) methylation, e.g., as a modifier of mitochondrial epigenetic mechanisms and mitochondrial functioning
Summary
The earliest understanding of the functional role of epigenetic mechanisms relates to developmental genome regulation; e.g., silencing of gene expression involved in cell differentiation and in maintaining cell phenotypes during cell proliferation [1,2,3,4,5,6]. These authors [42] proposed that DNMT3A (and possibly DNMT1) are up-regulated in ALS motor neurons, and that the increased DNMT activity and elevated DNA content of 5mC, possibly in mtDNA, may be an important component of ALS pathobiology and a putative target for drug development.
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