[Mitochondrial calcium regulation as a novel target for mood stabilizer development]

Bipolar disorder is a severe psychiatric disorder characterized by recurrent episodes of mania and depression. Although several mood stabilizers are available, their mechanisms of action remain incompletely understood, and no drugs have been developed based on the biological abnormalities underlying bipolar disorder. Accumulating evidence, including abnormalities in brain energy metabolism, mitochondrial DNA alterations, and the high prevalence of bipolar disorder among patients with mitochondrial diseases, has led to the mitochondrial dysfunction hypothesis of bipolar disorder. In addition, dysregulation of intracellular Ca²⁺ signaling has been repeatedly reported in patients with bipolar disorder, suggesting a potential role of mitochondrial calcium homeostasis in the pathophysiology of bipolar disorder. To explore novel therapeutic strategies, we focused on the mitochondrial permeability transition pore (mPTP), a key regulator linking mitochondrial calcium homeostasis and mitochondrial dysfunction. Previous studies using a mutant Polg1 transgenic mouse model, which accumulates mitochondrial DNA abnormalities in the brain, identified cyclophilin D (CypD: PPIF), a regulator of mPTP opening, as a potential therapeutic target. Pharmacological inhibition of CypD improved behavioral abnormalities in this model, supporting the therapeutic relevance of mPTP. Subsequently, an ex vivo screening system using isolated mouse brain mitochondria was established to identify compounds that inhibit mPTP opening. This approach led to the identification of seco-cycline D (SCD), an inhibitor of mPTP opening that also exhibited neuroprotective effects in a mouse model of cerebral ischemia. This review summarizes the rationale for targeting mitochondrial calcium regulation and discusses the potential of mPTP as a novel target for mood stabilizer development.