Mitochondrial DNA: a blind spot in neuroepigenetics

Neuroepigenetics, which includes nuclear DNA modifi cations, such as 5-methylcytosine and 5-hydroxymethylcytosine and modifi cations of nuclear proteins, such as histones, is emerging as the leading fi eld 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 DNA 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 the mechanisms of mitochondrial DNA methylation and hydroxymethylation, including the discovery of mitochondrial DNA-methyltransferases and the presence and 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 fi rst time evidence supporting the existence of these mechanisms and 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.