Mitochondrial D-loop Methylation Levels Inversely Correlate with Disease Duration in Amyotrophic Lateral Sclerosis

Abstract

Aim: To correlate mitochondrial D-loop region methylation levels and mtDNA copy number with disease duration in familial amyotrophic lateral sclerosis (ALS) patients. Patients & methods: The study population included 12 ALS patients with a mutation in SOD1 and 13 ALS patients with the C9orf72 hexanucleotide repeat expansion. Methylation levels of the D-loop region and mtDNA copy number were quantified using pyrosequencing and quantitative PCR, respectively. Results: We observed that D-loop methylation levels inversely correlated while mtDNA copy number positively correlated with disease duration. Conclusion: Considering the central role played by mitochondria in ALS, this preliminary study provides new knowledge for future studies aimed at identifying biomarkers of disease progression and new targets for therapeutic interventions.

Plain language summary

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease which leads to the patient’s death a few years after the onset of the first symptoms. There are currently no treatments to cure the disease, and the only drugs available are able to prolong patients’ lives by only a few months. Patients may have much variability in the presentation of symptoms, including different duration of disease. This study aims to research whether mitochondrial DNA methylation, a mechanism involved in the biology of the mitochondrion, is associated with the duration of the disease. We observed that methylation of mitochondrial DNA inversely correlates with the disease duration, providing new knowledge for future studies aimed at identifying biomarkers of disease progression.

Tweetable abstract

Peripheral blood mitochondrial DNA methylation inversely correlates with disease duration in amyotrophic lateral sclerosis patients.

Keywords::

• amyotrophic lateral sclerosis
• C9orf72
• D-loop region
• disease duration
• mitochondrial DNA methylation
• mtDNA copy number
• SOD1

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2023-0265

Author contributions

F Coppedè, A Stoccoro and L Migliore designed the study. L Mosca, C Lunetta, A Marocchi and F Gerardi collected the samples and provided the clinical data of the patients. A Stoccoro and A Smith performed the experiments. A Stoccoro, A Smith and K Lunnon generated the experimental data. A Stoccoro and F Coppedè wrote the manuscript. All authors edited the paper and approved the final manuscript.

Acknowledgments

The authors thank Associazione ‘Io corro con Giovanni’ www.iocorrocongiovanni.org; [email protected]; Paina di Giussano-Via IV Novembre 20-c/o Centro Associativo ‘Generazioni’, for their initial support for starting our research in SOD1 and C9orf72 families.

Financial disclosure

The present study was supported by the researcher’s intramural funds (ATENEO Funds, University of Pisa). 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

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

Ethical conduct of research

The Ethics Committee of Pisa University approved the study (protocol no. 14767/2018). Informed consent was obtained from all the patients before their inclusion in the study. The study was carried out according to the Declaration of Helsinki.

Additional information

Funding

The present study was supported by the researcher’s intramural funds (ATENEO Funds, University of Pisa). 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.