Background:Although mitochondria dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls (Non-psychiatry controls). We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes.Methods:Fourteen BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled for this study. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting.Results:One-Way ANCOVA after controlling for age, sex, body mass index (BMI), and smoking status showed that patients with BD present a decrease in the MHI compared to non-psychiatry controls, and higher ccf-mtDNA levels, which was negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, we also evaluated the relationship between MQC-related proteins with MHI and ccf-mtDNA. Our results showed that MHI negatively correlated with Fis-1 and positively with Opa-1 and LC3. Moreover, we found a negative correlation between ccf-mtDNA, Opa-1, and LC3 and a positive correlation between cff-mtDNA and Fis-1. Finally, we found that subjects with longer illness duration, higher depressive symptom scores, and worse functional status had lower MHI and higher ccf-mtDNA.Conclusion:In summary, the present findings corroborate previous studies and provide strong support for the hypothesis that mitochondrial regulation and function are integral parts of the pathogenesis of BD.