Lithium increases leukocyte mitochondrial complex I activity in bipolar disorder during depressive episodes

Different lines of evidence suggest that mitochondrial dysfunction may be implicated in bipolar disorder (BD) pathophysiology. Mitochondrial electron transport chain (ETC) is a key target to evaluate mitochondrial function, but its activity has never been assessed in unmedicated BD or during mood episodes. Also, lithium has been shown to increase ETC gene expression/activity in preclinical models and in postmortem brains of BD subjects, but to date, no study has evaluated lithium's direct effects on ETC activity in vivo. This study aims to evaluate leukocyte ETC complexes I-IV activities in acute depressive episode in BD (compared to controls) and the effect of lithium treatment on ETC activity. Subjects with short-term BD during a depressive episode (n = 25) were treated for 6 weeks with lithium. Leukocytes were collected at baseline and endpoint and mitochondrial ETC complexes I-IV activities were evaluated and compared to age-matched healthy controls (n = 24). Lithium significantly increased mitochondrial complex I activity from baseline to endpoint (p = 0.02), with no changes in other complexes after 6 weeks. Also, plasma lithium levels were significantly correlated to mitochondrial complex I activity after treatment (p = 0.003). Mitochondrial complexes I-IV activities did not differ during depressive episodes in BD compared to healthy controls. Our findings demonstrate for the first time an increase in mitochondrial ETC complex I activity in vivo after lithium treatment in BD, which was positively associated with plasma lithium levels. Further studies are warranted to clarify the potential role of this target in neuroprotection-related drug development.