High-throughput screen identifies a potent MCU activator boosting cardiac contractile bioenergetics
Mitochondrial Ca2+ uptake through the mitochondrial calcium uniporter complex (MCUc) 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. Here, we screened 1,280 bioactive compounds and identified…
A novel high-throughput screening method has identified CGP7930 as a potent and selective activator of mitochondrial Ca2+ uptake, specifically the mitochondrial calcium uniporter complex (MCUc) in cardiac cells. The compound directly stimulates MCU activity and enhances mitochondria-endoplasmic reticulum contact sites, facilitating inter-organellar Ca2+ transfer.
Crucially, CGP7930 boosts Ca2+-dependent activation of mitochondrial energy metabolism in cardiomyocytes, leading to improved contractile performance in mouse hearts. However, the benefits are contingent on the presence of functioning MCUs, as hearts from mice lacking the MCU complex do not exhibit increased ventricular contraction force upon CGP7930 infusion.
The study pinpointed Gln304 and Val307 in MICU1 as critical determinants of CGP7930's activity, highlighting the compound's specific targeting of this key subunit within the MCU complex.
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