Mitochondrial transfer mechanisms in mood disorders: A cellular and clinical investigation of MIRO and TRAK expression

Introduction

Mitochondrial dysfunction is associated with the pathophysiology of mood disorders, including bipolar disorder and major depressive disorder[1]. Rotenone, a mitochondrial respiratory chain Complex-I inhibitor, is widely used at low doses to induce mild mitochondrial stress in experimental mood disorder models[2]. Mitochondrial transfer, referring to the intercellular trafficking of healthy mitochondria, is an important cellular mechanism. In this process, Mitochondrial Rho GTPases 1 and 2 (MIRO1/MIRO2) and Trafficking Kinesin Proteins 1 and 2 (TRAK1/TRAK2) regulate mitochondrial movement along microtubules[3]. This study examined rotenone-induced changes in mitochondrial transfer, the modulatory effects of lithium, and related gene expression alterations in euthymic bipolar disorder (euthymic BD), unipolar depression (UD), and bipolar depression (BD).

Methods

An in vitro model of mitochondrial dysfunction was established in the human neuroblastoma SH-SY5Y cell line by exposure to 10 pM rotenone for 96 hours, with 1 mM lithium chloride administered during the final 48 hours. Cell viability was assessed by MTT assay. Expression levels of MIRO1, MIRO2, TRAK1, TRAK2, SOD2, NRF2, PINK1, PARKIN, MFN1, MFN2, PGC-1α, and TFAM were quantified by qPCR. The clinical cohort comprised 53 individuals with euthymic BD, 31 patients with current depression, including UD and BD-D, and 31 healthy controls (HC). Group differences in gene expression were analyzed using ANCOVA, with age, sex, and smoking status as covariates.

Results

In the cellular model, rotenone induced mild mitochondrial stress, evidenced by increased SOD2 and NRF2 expression, indicating activation of antioxidant defense mechanisms. Increased PGC-1α and TFAM supported a compensatory mitochondrial biogenesis response. Upregulation of PARKIN without significant PINK1 changes suggested an early mitochondrial quality-control response rather than clear transcriptional activation of canonical mitophagy. Increased MFN1 and MFN2 expression was consistent with a compensatory mitochondrial fusion response. MIRO1 and TRAK2 were upregulated, whereas MIRO2 and TRAK1 were downregulated, suggesting involvement of mitochondrial transfer mechanisms. Lithium co-treatment partially normalized these alterations. In the clinical cohort, MIRO2 and TRAK1 expression levels were significantly elevated in the depression group compared with healthy controls (p = 0.008), whereas MIRO1 and TRAK2 showed no significant differences. Subgroup analyses showed that MIRO2 expression was highest in the BD-D group, with significant increases relative to the UD group (p = 0.007) and healthy controls (p = 0.012). In contrast, TRAK1 expression was significantly elevated only in the UD group compared with healthy controls (p = 0.008). No significant alterations in MIRO1 or MIRO2 expression were observed in the euthymic BD group.

Conclusions

Distinct expression patterns of MIRO2 and TRAK1 in bipolar and unipolar depressive states suggest a state-dependent regulatory role of mitochondrial transfer pathways in mood disorders. The contrasting MIRO/TRAK changes observed in the cell model and active clinical episodes may reflect differences between acute mitochondrial stress responses and compensatory regulatory processes during disease progression. Partial normalization of MIRO/TRAK expression by lithium further supports its modulatory role in mitochondrial homeostasis and the relevance of these mechanisms. Findings from the euthymic bipolar group support this interpretation, suggesting that these pathways may be more involved during uncontrolled active disease phases than stable conditions.

References

1-Lam, X.-J., et al., Mitochondria dysfunction and bipolar disorder: From pathology to therapy. IBRO Neuroscience Reports, 2023. 14: p. 407-418. 2-Damri, O., et al., Using mitochondrial respiration inhibitors to design a novel model of bipolar disorder-like phenotype with construct, face and predictive validity. Translational psychiatry, 2021. 11(1): p. 123. 3-Davis, K., et al., Miro GTPase domains regulate the assembly of the mitochondrial motor–adaptor complex. Life Science Alliance, 2023. 6(1).