Bipolar disorder (BD) is a chronic alteration in emotional health characterized by swings between mania and depression. Mitochondrial mechanisms are increasingly understood to contribute to energy dysregulation in BD. Higher ATPase C-subunit leak channel (ACLC) activity causes a shift in metabolism of neurons from oxidative phosphorylation to aerobic glycolysis and could cause energy changes. We found ATP synthase c-subunit protein expression was increased relative to ATP synthase F1β subunit in both induced pluripotent stem cells and cortical organoids of BD patients. To determine if high ACLC predisposes to increased channel activity, we performed patch clamp recordings of mitochondrial inner membranes (mitoplasts) isolated from brain organoids of BD patients and healthy controls (HC). We found an increase in large, multi-conductance, voltage dependent channel activity. Lithium (Li) is an effective medication for BD. Although its exact mechanism is not fully understood, it was reported that Li inhibited mitochondrial permeability transition pore (mPTP) activity. We reported that mPTP is a multi-conductance channel comprised of ACLC and perhaps also the ADP/ATP translocase (AAC). We applied Li to the bath during isolated mitoplast recordings; Li attenuated the conductance in both BD and HC mitoplasts. The remainder of the conductance was reduced by known pharmacological inhibitors of inner membrane channels, including ACLC (dexpramipexole), AAC (bongkrekic acid), and ACLC (ATP). Dex also partially inhibited the conductance when added before Li. In recordings of purified ATP synthase reconstituted into lipid bilayers, small concentrations of Li inhibited channel activity, suggesting Li interacts directly with ATP synthase. Our study demonstrates that mitochondria of cortical organoids derived from BD patients exhibits channel activity of ATP synthase, AAC, and free c-subunit. These findings support a novel mechanism in BD pathophysiology and offer promising therapeutic strategies targeting mitochondrial leak channels to ameliorate clinical phenotypes.
Shen et al. (Sun,) studied this question.