Altered Mitochondrial DNA Methylation Pattern in Alzheimer Disease–Related Pathology and in Parkinson Disease

Abstract

Mitochondrial dysfunction is linked with the etiopathogenesis of Alzheimer disease and Parkinson disease. Mitochondria are intracellular organelles essential for cell viability and are characterized by the presence of the mitochondrial (mt)DNA. DNA methylation is a well-known epigenetic mechanism that regulates nuclear gene transcription. However, mtDNA methylation is not the subject of the same research attention. The present study shows the presence of mitochondrial 5-methylcytosine in CpG and non-CpG sites in the entorhinal cortex and substantia nigra of control human postmortem brains, using the 454 GS FLX Titanium pyrosequencer. Moreover, increased mitochondrial 5-methylcytosine levels are found in the D-loop region of mtDNA in the entorhinal cortex in brain samples with Alzheimer disease-related pathology (stages I to II and stages III to IV of Braak and Braak; n = 8) with respect to control cases. Interestingly, this region shows a dynamic pattern in the content of mitochondrial 5-methylcytosine in amyloid precursor protein/presenilin 1 mice along with Alzheimer disease pathology progression (3, 6, and 12 months of age). Finally, a loss of mitochondrial 5-methylcytosine levels in the D-loop region is found in the substantia nigra in Parkinson disease (n = 10) with respect to control cases. In summary, the present findings suggest mtDNA epigenetic modulation in human brain is vulnerable to neurodegenerative disease states.

Epigenetic regulation in Parkinson’s disease

“…Blanch et al,. reported loss of mitochondrial DNA 5-methylation levels in the substantia nigra of PD patients [4]. These finding could support the hypothesis that mitochondrial dysfunction is a common molecular mechanism in PD pathogenesis.…”

“…Additionally, a recent study showed that PD patients (n = 10) have a loss of m 5 C levels in the displacement loop (D-loop) of the substantia nigra mitochondrial DNA when compared with controls (n = 10) [4]. This could be attributable to dopaminergic neuronal loss in the substantia nigra, but methylation levels of mitochondrial NADH dehydrogenase 6 ( ND6 ) in this region were similar between PD patients and controls suggesting that the m 5 C methylation changes in the mitochondrial D-loop are not due to neuronal loss [4].…”

“…This could be attributable to dopaminergic neuronal loss in the substantia nigra, but methylation levels of mitochondrial NADH dehydrogenase 6 ( ND6 ) in this region were similar between PD patients and controls suggesting that the m 5 C methylation changes in the mitochondrial D-loop are not due to neuronal loss [4]. Interestingly, nuclear DNA is not the only type showing differential methylation patterns.…”

Experimental mitochondria-targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential regulator of mitochondrial gene expression

“…Therefore, this study aims to gain insight into functional effects of mtDNA methylation, if present at all. We hypothesize that differential mtDNA cytosine methylation affects mtDNA gene expression or mtDNA replication, and as such may contribute to the pathogenesis of various diseases 14, 16–19 . Here, we show that low levels of methylation can be detected in the mtDNA of various cancer cell lines and fibroblasts of a mtDNA disease patient.…”

Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue

“…However, most research is either focussed on low resolution, global DNA methylation, or candidate gene DNA methylation changes using techniques such as bisulfite pyrosequencing [20]. These recent publications have indicated that differences in mtDNA methylation are present in a variety of different phenotypes [24–29] and may have potential utility as a biomarker [30]. In addition, a recent study has explored the use of Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq) to investigate changes in mtDNA methylation across 39 cell lines and tissues from publicly available data [31].…”