Abstract
Mitochondrial impairment and increased oxidative stress are common features in neurodegenerative disorders, leading researchers to speculate that epigenetic changes in the mitochondrial DNA (mitoepigenetics) could contribute to neurodegeneration. The few studies performed so far to address this issue revealed impaired methylation levels of the mitochondrial regulatory region (D-loop region) in both animal models, postmortem brain regions, or circulating blood cells of patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Those studies also revealed that mtDNA D-loop methylation levels are subjected to a dynamic regulation within the progression of the neurodegenerative process, could be affected by certain neurodegenerative disease-causative mutations, and are inversely correlated with the mtDNA copy number. The methylation levels of other mtDNA regions than the D-loop have been scarcely investigated in human specimens from patients with neurodegenerative disorders or in animal models of the disease, and evidence of impaired methylation levels is often limited to a single study, making it difficult to clarify their correlation with mitochondrial dynamics and gene expression levels in these disorders. Overall, the preliminary results of the studies performed so far are encouraging making mitoepigenetics a timely and attractive field of investigation, but additional research is warranted to clarify the connections among epigenetic changes occurring in the mitochondrial genome, mitochondrial DNA dynamics and gene expression, and the neurodegenerative process.
Highlights
Mitochondria are small cytosolic organelles evolved from a symbiotic relation between aerobic bacteria and the primordial eukaryotic cells unable to use oxygen, developed about 1.5 billion years ago
Only a few studies have so far investigated mitoepigenetic changes in human specimens or animal models of neurodegenerative disorders, providing encouraging but still preliminary results (Table 1). Most of these studies investigated the methylation levels of the mitochondrial D-loop region [24, 37, 61, 62], and there is consensus in the literature that the methylation levels of this region correlate with the copy number of the mitochondrial DNA (mtDNA)
An inverse correlation between D-loop methylation levels and mtDNA copy number was observed in cancerous tissues [40], in human placenta [41], and in peripheral blood DNA samples [35, 36, 38, 39], including blood DNA samples of patients with neurodegenerative diseases [37]
Summary
Mitochondria are small cytosolic organelles evolved from a symbiotic relation between aerobic bacteria and the primordial eukaryotic cells unable to use oxygen, developed about 1.5 billion years ago. Increasing evidence suggests that changes in DNA methylation and hydroxymethylation occur in the mtDNA, and represent epigenetic modifications of the mitochondrial genome (mitoepigenetics) likely regulating both mtDNA replication and gene expression levels [11]. The rapid development of novel techniques for the study of nuclear DNA methylation, adapted for the study of mitochondrial epigenetic mechanisms, made possible to apply several different methods to investigate mtDNA methylation and hydroxymethylaytion Some of such methods require the purification of mitochondria (e.g., mass spectrometry and ELISA approaches) and detection of epigenetic marks is carried out by using antibodies against 5-mC or 5-hmC. Variations in mtDNA methylation patterns have been associated to various endogenous metabolites, including thyroid hormones
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