Increased mitochondrial DNA copy number in bipolar disorder but not in unaffected siblings

Introduction and Aims: Bipolar disorder (BD) is a chronic psychiatric illness characterized by recurrent mood episodes and significant functional impairment. Mitochondrial dysfunction has emerged as a key candidate mechanism, with alterations in mitochondrial DNA (mtDNA) copy number, epigenetic regulation, and oxidative stress reported in BD. This study aimed to investigate whether mtDNA copy number differs between individuals with BD, their unaffected first-degree siblings (SIB), and healthy controls (HC).

Methods: Participants underwent structured clinical interviews prior to biological sampling. Individuals with BD were in a euthymic state at the time of assessment, as confirmed by standardized rating scales. Fasting peripheral blood samples were obtained from individuals with BD (n = 74), SIB (n = 55), and HC (n = 86). Peripheral blood mononuclear cells were isolated for genomic DNA extraction. mtDNA copy number was quantified using quantitative polymerase chain reaction as the ratio of mtDNA to a single-copy nuclear gene. mtDNA copy number values were log-transformed. Clinical assessments included structured diagnostic interviews (e.g., SCID) and validated rating scales to evaluate mood symptoms, such as the Young Mania Rating Scale, Hamilton Depression Rating Scale and Perceived Stress Scale, and lifestyle factor (Health-Promoting Lifestyle Profile II; HPLP-II). Group differences and associations between mtDNA copy number and clinical variables were examined using covariate-adjusted analysis of covariance and linear regression models, with adjustment for age, sex, body mass index (BMI), and HPLP-II.

Results: The sample was 66.2% female, with similar sex distribution across groups. The BD group was older than HC (39.41 ± 10.65 vs. 33.69 ± 8.86 years, p < 0.001), with no differences between BD–SIB or SIB–HC. BMI was higher in BD (28.95 ± 5.49 kg/m²) compared with SIB (24.46 ± 3.58 kg/m²) and HC (23.60 ± 3.95 kg/m²) (both p < 0.001), while SIB and HC did not differ. HPLP-II total scores differed significantly across the groups (HC > SIB > BD, all for p ≤ 0.017). Young Mania Rating Scale, Hamilton Depression Rating Scale and Perceived Stress Scale scores did not differ across groups. Mean mtDNA copy number was highest in the BD group (76.71 ± 55.10), followed by HC (73.31 ± 97.20) and SIB (63.84 ± 47.10). MtDNA copy number was significantly higher in the BD group compared with both SIB and HC (p= 0.009 and p= 0.049, respectively), with no difference between SIB and HC (p= 0.483). In the BD group, mtDNA copy number was significantly associated with a lower number of manic episodes (β = −0.234, p= 0.041) and male sex (β = 0.284, p= 0.017), while age, BMI, and HPLP-II scores were not significant predictors (all p > 0.05).

Conclusion: The higher mtDNA copy number observed in individuals with bipolar disorder, in the absence of differences in unaffected siblings, may suggest that this alteration is related to illness processes rather than familial vulnerability. The negative association with manic episode number suggests that mtDNA copy number may be related to illness burden. Overall, these findings indicate that mitochondrial alterations may be associated with BD and its clinical characteristics.

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