Investigating Mitochondria in the Mechanism of Lithium Response in Bipolar Disorder

Bipolar disorder (BD), a severe mood disorder, affects millions of patients worldwide, yet the link from genetic risk to disease biology and treatment response remains unclear. Hundreds of genetic risk loci are implicated, while converging evidence from patients and patient-derived cellular models points to mitochondrial dysfunction, altered neuronal excitability, disrupted calcium signaling, and abnormal neurodevelopment in BD pathophysiology. Lithium, the first-line treatment, tentatively rescues several of these phenotypes in response-specific models, but its mechanisms remain incompletely understood. We hypothesize that BD is partially due to an imbalance between proliferation and differentiation during development due to genetic factors and mitochondrial dysfunction. This will lead to impaired stress tolerance and energy metabolism that can be relieved by lithium.