Mitochondrial Epigenetics and Neurodegeneration
Mitochondrial impairment is a feature of neurodegeneration and many investigators have suggested that epigenetic modifications of the mitochondrial DNA (mtDNA) might occur in Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative conditions, but evidence in humans is limited. There is accumulating evidence of epigenetic modifications in samples from patients with neurodegenerative diseases. However, data are mainly available from changes occurring in nuclear chromatin or DNA.
A recent study investigated mtDNA methylation in post-mortem samples and revealed increased methylation of the mitochondrial displacement loop (D-loop) region, a region critical for mtDNA replication and transcription, in the entorhinal cortex of eight patients with AD-related pathology (stages I/II and III/IV of Braak). The degree of methylation was higher in early disease stages than in later stages. These results were corroborated by a dynamic pattern of methylation of this region that was observed in transgenic AD mice (APP/PS1 mice) along with disease progression1. Similarly, decreased D-loop methylation levels were observed in the substantia nigra of ten patients with PD respect to healthy matched controls. Collectively, these data suggest that the degree of methylation of this region might characterize different stages of the neurodegenerative process1. Moreover, it was demonstrated that mtDNA methylation patterns are abnormal in skeletal muscle and spinal cord of presymptomatic amyotrophic lateral sclerosis mice (transgenic SOD1 mice), and that these abnormalities occur in parallel with loss of myofiber mitochondria2.
To further address this issue we assessed the methylation levels of the mtDNA D-loop region in blood DNA samples from 133 living AD patients and 130 matched controls. We observed a significant 25% reduction of methylation levels in the first group3, thus strengthening previous evidence that epigenetic modifications of the mtDNA might occur in neurodegeneration. Further studies are now required to confirm these findings and to explore the factors likely contributing to the observed changes and their pathological consequences.
Stoccoro A, Siciliano G, Migliore L, Coppedè F. Decreased Methylation of the Mitochondrial D-Loop Region in Late-Onset Alzheimer’s Disease. J Alzheimers Dis. 2017 Jun 22. 59 (2), 559-564.
1) Blanch M, Mosquera JL, Ansoleaga B, Ferrer I, Barrachina M (2016) Altered Mitochondrial DNA Methylation Pattern in Alzheimer Disease-Related Pathology and in Parkinson Disease. Am J Pathol 186, 385-97.
2) Wong M, Gertz B, Chestnut BA, Martin LJ. Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front Cell Neurosci. 2013 Dec 25;7:279.
3) Stoccoro A, Siciliano G, Migliore L, Coppedè F. Decreased Methylation of the Mitochondrial D-Loop Region in Late-Onset Alzheimer’s Disease. J Alzheimers Dis. 2017 Jun 22. 59 (2), 559-564.