Mitochondrial Insights into Lithium Response in Bipolar Disorder: A State-of-the-Art Review

: Bipolar disorder (BD) is a severe, recurrent mood disorder associated with mitochondrial and bioenergetic dysfunction, which may contribute to both symptom expression and variability in treatment response. Although lithium remains the gold standard treatment, a significant proportion of patients fail to achieve full benefit, and reliable predictive biomarkers are still lacking. Increasing evidence suggests that lithium exerts part of its therapeutic effects through modulation of mitochondrial function, including enhanced oxidative phosphorylation, regulation of mitochondrial dynamics, and reduction of oxidative stress. In this state-of-the-art review, we synthesize the current literature on the relationship between lithium and mitochondrial function, with the aim of evaluating how this relationship may inform our understanding of lithium response in BD. We reviewed findings on mitochondrial bioenergetics, oxidative stress, and mitochondrial DNA alterations, and discussed the roles of key regulatory proteins such as Drp1, Opa1, Mfn2, and Nrf2. In addition, we explore peripheral and epigenetic biomarkers, including mitochondrial DNA D-loop methylation, microRNAs and a potential therapeutic target ⎻ mitochondrial transfer mechanism. In addition to synthesizing the existing literature, we identify key gaps that hinder progress, such as clinical studies being predominantly cross-sectional, lacking standardized mitochondrial assessments, and rarely employing longitudinal or genetically informed designs like mitochondrial twin studies. We highlight the need for unified protocols, integration of omics technologies, extracellular vesicle-based sampling strategies, and improved in vitro and in vivo models. A better understanding of mitochondrial signatures related to lithium may enable biomarker discovery and advance personalized treatment in BD.