Berberine is a novel mitochondrial calcium uniporter (MCU) inhibitor that disrupts MCU-EMRE assembly

The mitochondrial calcium uniporter (MCU) complex, localized in the inner mitochondrial membrane, plays a crucial role in regulating mitochondrial Ca2+ influx, thereby impacting cellular energy metabolism and apoptosis. Dysregulation of mitochondrial calcium levels is implicated in various diseases, including neurodegenerative disorders, cardiac diseases and cancer. Despite the critical roles of MCU, developing specific and clinically viable inhibitors has been challenging. Here, we identify Berberine, a well-established drug with a documented safety profile, as a potent MCU inhibitor. Utilizing virtual screening of an FDA-approved drug library, we discovered Berberine's significant inhibitory effect on MCU. Mechanistically, Berberine localizes within mitochondria and binds near the MCU's juxtamembrane loop (JML) domain. This binding disrupts the interaction of MCU with its essential regulator, EMRE, thereby inhibiting rapid Ca2+ entry into the mitochondrial matrix. Notably, Berberine pretreatment reduced mitochondrial Ca2+ overload and mitigated ischemia/reperfusion-induced myocardial injury in a murine model. Our findings establish Berberine as a potent MCU inhibitor, offering a potential therapeutic avenue for diseases associated with dysregulated mitochondrial calcium homeostasis.