Differential effects of lithium on metabolic dysfunction in astrocytes derived from bipolar disorder patients

Metabolic alterations have been observed in the brains of patients with bipolar disorder (BD), a neuropsychiatric disorder characterized by biphasic mood episodes of mania and depression. However, the specific contributions of glial cells to these metabolic changes in BD patients remain largely unknown and have not been extensively studied. Here, we investigate the metabolic characteristics of induced astrocytes (iAstrocytes) derived from induced pluripotent stem cells of BD patients and their responses to lithium treatment. The gene expression profiles of iAstrocytes from BD patients (BD iAstrocytes) indicate dysregulation of metabolic processes in BD iAstrocytes. Compared to iAstrocytes from control subjects, BD iAstrocytes showed decreased mitochondrial respiration, increased glycolysis, and elevated lactate secretion. These changes in metabolic pathways suggest impaired mitochondrial function. Additionally, we observed reduced protein expression within the oxidative phosphorylation complex and decreased reactive oxygen species production, further supporting the impaired mitochondrial function in BD iAstrocytes. Intriguingly, BD iAstrocytes showed an accumulation of lipid droplets (LDs) in both volume and number, possibly reflecting metabolic stress-induced LD accumulation. Lithium, a commonly prescribed treatment for BD, selectively attenuated LD accumulation exclusively in BD iAstrocytes from lithium responders, while it failed to restore mitochondrial dysfunction and increased lactate secretion. Our findings provide novel insights into understanding the metabolic dysfunction in the brains of BD patients and shed light on molecular mechanisms of lithium action, particularly regarding astrocytes. The LDs in BD iAstrocytes from lithium non-responders may serve as a useful readout for drug screening to identify suitable medications for these patients.