Increase in Mitochondrial D-Loop Region Methylation Levels in Mild Cognitive Impairment Individuals

Abstract

Methylation levels of the mitochondrial displacement loop (D-loop) region have been reported to be altered in the brain and blood of Alzheimer’s disease (AD) patients. Moreover, a dynamic D-loop methylation pattern was observed in the brain of transgenic AD mice along with disease progression. However, investigations on the blood cells of AD patients in the prodromal phases of the disease have not been performed so far. The aim of this study was to analyze D-loop methylation levels by means of the MS-HRM technique in the peripheral blood cells of 14 mild cognitive impairment (MCI) patients, 18 early stage AD patients, 70 advanced stage AD patients, and 105 healthy control subjects. We found higher D-loop methylation levels in MCI patients than in control subjects and AD patients. Moreover, higher D-loop methylation levels were observed in control subjects than in AD patients in advanced stages of the disease, but not in those at early stages. The present pilot study shows that peripheral D-loop methylation levels differ in patients at different stages of AD pathology, suggesting that further studies deserve to be performed in order to validate the usefulness of D-loop methylation analysis as a peripheral biomarker for the early detection of AD.

Integrating mitoepigenetics into research in mood disorders: a state-of-the-art review

“…( Bellizzi et al, 2013 ; Dostal and Churchill, 2019 ). MtDNA methylation and hydroxymethylation have been shown that these changes have effects on neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis ( Blanch et al, 2016 ; Stoccoro et al, 2018 ; Nikolac Perkovic et al, 2021 ; Stoccoro and Coppedè, 2021 ; Stoccoro et al, 2022 ). Several animal studies have shown TET-mediated antidepressant-like effects, but most of them are related to nuclear epigenetic regulation.…”

Mitochondrial One-Carbon Metabolism and Alzheimer’s Disease

“…The D-loop region of the mitochondrial genome regulates the replication of mtDNA and its transcription [ 141 , 142 , 143 , 144 ] and is methylated in both model animals and humans [ 145 , 146 ]. Both the hypo- and hypermethylation of the D loop have been observed in AD [ 138 , 140 , 147 ]. This variation in the degree of methylation might be explained by variations in disease stage or the brain area used for the analysis.…”

Epigenetic Peripheral Biomarkers for Early Diagnosis of Alzheimer’s Disease

“…The BIN1 gene, encoding for the bridging integrator 1, is the second most important susceptibility gene for late-onset AD after the APOE gene, and interestingly, two large independent autopsy studies showed that there were methylation changes in the BIN1 of the AD patient’s brain, accompanied by high expression of BIN1 [ 41 , 70 ]. We recently identified mtDNA higher D-loop methylation levels, which regulates both mtDNA replication and gene expression, in MCI patients characterized by neurological examination, CSF biomarkers, and neuroimaging analyses compared to control subjects and AD patients at both early and advanced stages of the disease [ 71 ]. Moreover, higher D-loop methylation levels were detected in controls compared to AD patients in advanced stages of the disease, but not in those at early stages.…”

“…Similarly, in recent years we have seen increasing evidence that epigenetic modifications of mitochondrial DNA (mitoepigenetics) also likely play a significant role in the etiology of several human diseases, including cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases [ 113 ]. However, until now only one study investigated mitoepigenetic modifications in the peripheral blood of patients with MCI [ 71 ], and results suggest that this field of research deserves to be further investigated. Another issue that should be addressed in future studies is the investigation of environmental factors to which individuals have been exposed during their life, since they can play an important role in the etiology of AD [ 114 ].…”