Targeting ATP synthase c-subunit leak reverses brain metabolism of bipolar disorder

Bipolar Disorder (BD) is characterized by dysregulated emotional and energy states and is associated with abnormal mitochondrial function and elevated lactate levels in serum, cerebrospinal fluid, and brain tissue. Here, we report that induced pluripotent stem cells (iPSCs) and human cortical organoids (hCOs) derived from individuals with BD exhibit upregulation of the ATP synthase c-subunit (ACLC), leading to increased aerobic glycolytic leak metabolism. BD-hCOs display elevated lactate secretion, enhanced protein synthesis, increased ribosomal biogenesis, and disrupted ventricular zone architecture, consistent with early neurodevelopmental abnormalities. Both treatment with lithium, a first-line therapy for BD, and Dexpramipexole (Dex), a known ATP synthase inhibitor, suppressed ACLC-mediated conductance and reduced metabolic leak, protein synthesis, and hCO hyperexcitability. Consistent with these in vitro findings, in vivo data from individuals with BD revealed elevated blood lactate levels and neuroimaging markers of increased brain oxidative metabolism. These results implicate ACLC as a treatable driver of metabolic, electrophysiological, and structural brain developmental abnormalities in BD.