Structure-Activity Relationships of Metal-Based Inhibitors of the Mitochondrial Calcium Uniporter

The mitochondrial calcium uniporter (MCU) is a transmembrane protein that is responsible for mediating mitochondrial calcium (mCa²⁺ ) uptake. Given this critical function, the MCU has been implicated as an important target for addressing various human diseases. As such, there has a been growing interest in developing small molecules that can inhibit this protein. To date, metal coordination complexes, particularly multinuclear ruthenium complexes, are the most widely investigated MCU inhibitors due to both their potent inhibitory activities as well as their longstanding use for this application. Recent efforts have expanded the metal-based toolkit for MCU inhibition. This concept paper summarizes the development of new metal-based inhibitors of the MCU and their structure-activity relationships in the context of improving their potential for therapeutic use in managing human diseases related to mCa²⁺ dysregulation.