A novel mitochondrial target as a therapeutic approach to bipolar disorder

Neurons derived from patient induced pluripotent stem cells, (iPSCs) have been used to model psychiatric disorders. Stem cell-derived 3D human brain organoids have the potential to recapitulate features of the human brain with greater complexity than 2D models and are increasingly being applied to model diseases affecting the central nervous system. Studies of hippocampal dentate gyrus-like neurons derived from patients with bipolar disorder have previously revealed mitochondrial abnormalities and neuronal hyperexcitability compared with healthy controls (HCs). Our lab had shown that neurons from an autism model mouse and patient cells had a leak in the ATP synthase in the inner mitochondrial membrane caused in part byan imbalance of ATP synthase components. The membrane embedded portion of the ATP synthase (c-subunit ring) was found to be overexpressed compared to the assembled ATP synthase and this contributed to formation of a leaky channel. We found ATP synthase stoichiometry was affected in bipolar disorder (BD) patient-derived neurons. We found ATP synthase β-subunit was not significantly changed while c-subunit was significantly increased in both types of organoids compared to those of the HC. In the iPSCs, we also found enhanced c-subunit expression. From electron microscopic images, we found BD neurites and somata have smaller and less electron dense mitochondria. We found that mitoplasts isolated from BD organoids demonstrated increased leak channel activity compared to mitoplasts isolated from HC organoids. The activity inboth groups was sensitive to Li+, the ATP synthase modulator Dexpramipexole, the ANT inhibitor bongkrekic acid and to c-subunit leak channel inhibitor ATP. We hypothesize the normal aerobic glycolytic metabolism of developing neuronsis increased or persistent in BD neurons caused by several leak channels, leading to a persistent glycolytic metabolic phenotype at later developmental stages with high lactate production and reversal of ATP synthase to the hydrolytic mode. Our findings may indicate changes in metabolic activity (leak metabolism)in BD patient brain organoids.