Polymorphisms of Genes Required for Methionine Synthesis and DNA Methylation Influence Mitochondrial DNA Methylation

Abstract

Aim: Impaired methylation of the mitochondrial DNA and particularly in the regulatory displacement loop (D-loop) region, is increasingly observed in patients with neurodegenerative disorders. The present study aims to investigate if common polymorphisms of genes required for one-carbon metabolism (MTHFR, MTRR, MTR and RFC-1) and DNA methylation reactions (DNMT1, DNMT3A and DNMT3B) influence D-loop methylation levels. Materials & methods: D-loop methylation data were available from 133 late-onset Alzheimer’s disease patients and 130 matched controls. Genotyping was performed with PCR-RFLP or high resolution melting techniques. Results: Both MTRR 66A > G and DNMT3A -448A > G polymorphisms were significantly associated with D-loop methylation levels. Conclusion: This exploratory study suggests that MTRR and DNMT3A polymorphisms influence mitochondrial DNA methylation; further research is required to better address this issue.

Keywords::

• Alzheimer’s disease
• D-loop methylation
• DNMT3A
• mitochondrial DNA methylation
• mitoepigenetics
• MTHFR
• MTR
• MTRR
• polymorphism
• RFC-1

Acknowledgments

The authors gratefully acknowledge the patients and the healthy control subjects as well as the Medical staff of the Pisa University Hospital for their cooperation.

Financial & competing interests disclosure

This work was partially supported by the Italian Ministry of Health (grant GR-2009-1606229 to F Coppedè) and by the senior researcher’s intramural funds (ATENEO Funds 2018, University of Pisa). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

his work was partially supported by the Italian Ministry of Health (grant GR-2009-1606229 to F Coppedè) and by the senior researcher’s intramural funds (ATENEO Funds 2018, University of Pisa). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.