MitomiR-5 is associated with mitochondrial biogenesis and illness burden in bipolar disorder

Introduction

Bipolar disorder has been increasingly linked to mitochondrial dysfunction. However, the molecular mechanisms connecting mitochondrial regulation to clinical course and illness burden remain unclear. Mitochondrial genome-encoded microRNAs (mitomiRs) may represent a novel regulatory layer linking mitochondrial dysfunction to disease expression.

Aims

This study investigated whether the mitochondrial genome-encoded microRNA mitomiR-5, predicted to target mitochondrial biogenesis–related genes (PGC1A, MTCO1, MTCO2), is associated with mitochondrial biogenesis and clinical illness burden in bipolar disorder. Additionally, its functional role was examined in an SH-SY5Y neuroblastoma cell line.

Methods

Participants underwent structured clinical interviews prior to sampling. Fasting peripheral blood samples were collected from individuals with bipolar disorder (BD; n=49), unaffected siblings (SIB; n=50), and healthy controls (HC; n=50). Peripheral blood mononuclear cells were used to assess expression levels of mitomiR-5 and mitochondrial biogenesis–related genes (PGC1A, MTCO1, MTCO2, POLG, TFAM, POLRMT, NRF1, SSBP1, TFB2M). Normality was assessed using the Shapiro–Wilk test. Group differences were analyzed using Quade nonparametric ANCOVA, with Benjamini–Hochberg correction and Holm–Bonferroni-adjusted post hoc tests. Associations with clinical variables were evaluated using Spearman correlations and linear regression models. All analyses were adjusted for age, sex, body mass index, and smoking status. In parallel, SH-SY5Y cells were transfected with a mitomiR-5 inhibitor to assess its functional effects on mitochondrial biogenesis–related gene expression.

Results

There were no significant differences between groups in age or sex. Significant group differences were observed for mitomiR-5, PGC1A, and MTCO1 after multiple comparison correction. MitomiR-5 expression was higher in BD compared to HC (p = 0.002) and SIB (p = 0.013). PGC1A and MTCO1 levels were elevated in BD compared to HC (both p = 0.001), while MTCO1 also differed between BD and SIB (p = 0.026). In BD, mitomiR-5 expression was negatively associated with the number of hypomanic episodes (r = -0.541, p < 0.001) and positively correlated with mitochondrial biogenesis markers, including PGC1A (r = 0.544, p < 0.001) and MTCO1 (r = 0.482, p < 0.001). TFB2M expression was positively associated with depressive symptom severity (r = 0.379, p = 0.007) and negatively with age at onset (r = -0.371, p = 0.009). POLRMT expression correlated positively with lithium response (Alda score; r = 0.392, p = 0.005). Regression analyses showed that mitomiR-5 independently predicted hypomanic episode number (β = -0.465, p = 0.002) and was independently associated with PGC1A (β = 0.592, p < 0.001) and MTCO1 (β = 0.700, p < 0.001) in BD group. TFB2M was independently associated with depressive symptom severity (β = 0.313, p = 0.048). In vitro, mitomiR-5 inhibition increased mitochondrial biogenesis–related gene expression, while mitochondrial DNA copy number remained unchanged.

Conclusions

These findings indicate that mitomiR-5 is associated with both mitochondrial biogenesis and clinical illness burden in bipolar disorder. The observed relationships suggest a potential link between mitochondrial regulation and disease severity. Further studies are needed to clarify the underlying mechanisms and clinical implications.

References

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