State-dependent alterations in circulating mitochondrial DNA copy number and common deletion in bipolar disorder

• Plasma and EV mtDNA copy numbers were reduced in dBD compared to rBD. • MtDNA common deletion was increased in both plasma and EVs during depression. • Plasma and EV mtDNA levels were strongly correlated, with ∼30% of mtDNA in EVs. • Plasma IL-6 was lower in depression, but not associated with mtDNA measures. • Findings suggest state-dependent mitochondrial dysfunction as a biomarker in BD. Mitochondrial dysfunction has been increasingly implicated in the pathophysiology of bipolar disorder (BD), and circulating mitochondrial DNA (mtDNA) has emerged as a potential biomarker. However, the biological significance of distinct circulating forms, structural abnormalities, and their association with inflammatory cytokines remains unclear. This study aimed to (1) quantify plasma mtDNA and extracellular vesicle-associated mtDNA (EV mtDNA), examine their correlations, and assess associations with interleukin-6 (IL-6), and (2) evaluate state-dependent alterations in the 4, 977-bp common deletion. Twenty-one paired plasma samples were collected longitudinally from BD patients during depressive (dBD) and remitted (rBD) states. Plasma and EV mtDNA copy numbers and the 4, 977-bp common deletion were quantified using multiplex qPCR. Plasma IL-6 levels were measured by ELISA. Data were normalized using median normalization. Plasma and EV mtDNA copy numbers were significantly reduced in dBD compared with rBD (PFDR < 0. 01 for both). In contrast, ND4/ND1 ratio was significantly lower in dBD in both plasma and EV fractions (PFDR < 0. 001 for both). Plasma and EV mtDNA levels were strongly correlated in both states, with EV mtDNA comprising ∼30% of total circulating mtDNA. Plasma IL-6 levels were decreased in dBD (PFDR < 0. 01) but showed no significant correlations with mtDNA measures. Depressive states in BD are associated with reduced circulating mtDNA copy number and increased common deletion compared with remission. Combined assessment of mtDNA abundance and integrity across extracellular compartments may represent a novel biomarker strategy for state-dependent mitochondrial dysfunction in BD.