Mitochondrial remodeling by lithium drives CD4⁺ naïve T cell fate and immune homeostasis in bipolar disorder

Immune signaling and mitochondrial redox biology have been implicated in bipolar disorder (BD), but the relationship between the clinical efficacy of lithium (Li) and immune dysfunction remains unclear.

We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from BD patients during the manic phase before and after Li treatment, and conducted Li intervention experiments in a mouse model exhibiting BD manic-like behaviors (BD-manic). At the cellular level, we assessed mitochondrial metabolic and bioenergetic parameters in CD4⁺ naïve T cells, along with the distribution of T cell subsets. We further measured peripheral cytokines and central nervous system inflammatory markers to characterize peripheral and central inflammatory changes.

Transcriptomic analysis of PBMCs from BD patients before and after Li treatment revealed significant alterations in metabolic pathways. In BD-manic mice, CD4⁺ naïve T cells exhibited metabolic alterations characterized by reduced mitochondrial membrane potential, decreased ATP production, impaired glucose uptake, increased ROS accumulation, and mitochondrial fragmentation compared with Control. These abnormalities were accompanied by increased total Drp1 expression, enhanced Drp1 Ser616 phosphorylation, and reduced Mfn2/Opa1 expression. Relative to BD-manic mice, Li treatment improved behavioral abnormalities, partially restored mitochondrial structure and bioenergetic function, and was associated with T cell subsets distribution. Li also reduced peripheral pro-inflammatory cytokines and attenuated hippocampal IL-6 expression, accompanied by amelioration of neuronal and microglial abnormalities.

These findings indicate that Li treatment is accompanied by mitochondrial remodeling in CD4⁺ naïve T cells together with peripheral immune and central inflammatory changes in BD.