High-throughput screen identifies a potent MCU activator boosting cardiac contractile bioenergetics

Mitochondrial Ca ²⁺ uptake is an evolutionarily conserved mechanism mediated by the mitochondrial calcium uniporter complex (MCUc) that couples intracellular Ca²⁺ signaling to energy metabolism and cellular function. Despite its physiological importance, potent and selective pharmacological activators of the MCU complex remain scarce, and existing compounds show modest specificity or poorly explored mechanisms. Here, we performed a high-content screen of 1,280 bioactive compounds and identified CGP7930 as a potent activator of mitochondrial Ca²⁺ uptake. Mechanistically, the compound required MICU1, but not MICU2, to exert its effects. Molecular docking, analysis of the topology of electron density (ρ) to explore the Non-Covalent Interaction (NCI) index, and site-directed mutagenesis identified a critical interaction site within MICU1 involving residues Gln304 and Val307. In addition to directly stimulating MCU activity, CGP7930 increased mitochondria-endoplasmic reticulum contact sites, suggesting an additional mechanism to facilitate inter-organellar Ca²⁺ transfer. CGP7930 promoted Ca ²⁺ -dependent activation of mitochondrial energy metabolism in cardiomyocytes and boosted the contractile performance of the mice hearts. This effect was MCU-dependent, as hearts from MCU KO mice failed to increase the ventricular contraction force upon CGP7930 perfusion. We conclude that MICU1 is a druggable regulatory target for modulating mitochondrial Ca²⁺ signaling, and that CGP7930 is a new potent activator of the MCU that promotes excitation-bioenergetics-contraction coupling in the heart.