Year: 2026
Type: article
Study design: Observational Study
Abstract: Introduction: Major Depressive Disorder (MDD) is a psychiatric disorder associated with genetic and epigenetic mechanisms, in which mitochondrial dysfunction has emerged as a prominent feature.Methylation changes in the D-loop region of mitochondrial DNA (mtDNA), which is involved in the regulation of replication and transcription, have been investigated in only a limited number of studies in MDD, with inconsistent findings (1,2,3).This study aimed to evaluate D-loop methylation in mtDNA obtained from neuron-derived extracellular vesicles (NDEVs) in MDD using a sequencingbased approach.Method: The study included 24 patients with MDD confirmed using the Structured Clinical Interview for DSM-IV (SCID) and 31 age-and sex-matched healthy volunteers with no lifetime psychiatric diagnosis.Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS), and additional clinical and psychosocial scales were administered.Extracellular vesicles were isolated from fasting venous blood samples, and NDEVs were enriched using the NCAM/CD56 immunocapture ethod.Vesicle characterization was confirmed by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blot.Methylation of eight CpG loci in the D-loop region of NDEV-derived mtDNA was analyzed by targeted sequencing following bisulfite conversion.Individual CpG methylation levels and the global D-loop methylation factor (MF) derived from principal component analysis were evaluated; age, sex, smoking status, and body mass index were included as covariates in the analyses.Results: The groups were comparable in terms of demographic variables.The MDD group had higher HDRS and Perceived Stress Scale scores, and lower Health-Promoting Lifestyle Profile scores.NDEV characterization supported appropriate isolation, and no group differences were observed in vesicle size or concentration.After controlling for covariates, the global D-loop MF was significantly higher in the MDD group (p=0.027).In individual analyses, significant differences were observed at the CpG6 (p<0.001) and CpG8 (p=0.007)loci.A positive and significant correlation was found between the D-loop MF and total HDRS score (Spearman's ρ=0.505, p<0.001).In multivariable linear regression analysis, total HDRS score was identified as the only independent variable associated with the global D-loop methylation factor (β=0.400, p=0.008). Conclusion:The positive association between Dloop methylation and depression severity suggests that mitochondrial methylation may be linked to the biological basis of depression.
Source: Journal of Clinical Psychiatry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7223180500