AUTHOR=Koh Mei Xin , Simpson Timothy , Zain Shamsul Mohd , Ayub Qasim , Cheah Hong Leong , Pan Yan , Cheng Shi Hui , Pung Yuh-Fen 

TITLE=Mitochondrial DNA Mutations and Epigenetic Regulation in Type 2 Diabetes Mellitus Development

JOURNAL=British Journal of Biomedical Science

VOLUME=Volume 82 - 2025

YEAR=2025

URL=https://www.frontierspartnerships.org/journals/british-journal-of-biomedical-science/articles/10.3389/bjbs.2025.15375

DOI=10.3389/bjbs.2025.15375

ISSN=2474-0896

ABSTRACT=The global prevalence of type 2 diabetes mellitus (T2DM) has increased significantly over the past decade and is projected to rise further. While genetic and lifestyle factors are well-established contributors to T2DM pathogenesis, mitochondria have also gained attention as the key players. Many studies suggested that mitochondrial DNA (mtDNA) mutations and epigenetic modifications were implicated in the development and progression of T2DM. This review aimed to provide a comprehensive analysis of mtDNA mutations and epigenetic modifications associated with T2DM. Based on data from 30 published studies, a total of 117 mtDNA mutations were identified to be associated with T2DM, with D-loop region being the mutation hotspot. However, it was reported that the majority of D-loop mutations were also more frequently observed in healthy populations compared to mutations in other mtDNA regions, suggesting their potential non-pathogenic characteristic. Thus, mtDNA mutations found to be associated with T2DM but with lower occurrence in healthy populations may play a more significant role in influencing T2DM susceptibility. Regarding epigenetic modifications, mtDNA methylation was commonly reported in the D-loop and ND6 regions across seven studies. These findings suggested that these regions may play critical roles in the regulation of mitochondrial gene expression under diabetic conditions. Lastly, this review also discussed the technical challenges and limitations of detecting mtDNA mutations and methylation changes. In addition, relevant ethical considerations surrounding mitochondrial genetic research were also addressed. In conclusion, mtDNA mutations and methylation changes could potentially serve as biomarkers for the development and progression of T2DM. These molecular modifications may offer valuable insights for early diagnosis and preventive strategies. However, further research and validation are essential to establish their clinical significance and diagnostic utility.