Search for: All records

Abstract 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 tomCa²⁺dysregulation. 

An analogue of the mitochondrial calcium uniporter (MCU) inhibitor Ru265 containing axial ferrocenecarboxylate ligands is reported. This new complex exhibits enhanced cellular uptake compared to the parent compound Ru265. 

Infrared spectroscopy has drawn considerable interest in biological applications, but the measurement of live cells is impeded by the attenuation of infrared light in water. Metasurface-enhanced infrared reflection spectroscopy (MEIRS) had been shown to mitigate the problem, enhance the cellular infrared signal through surface-enhanced infrared absorption, and encode the cellular vibrational signatures in the reflectance spectrum at the same time. In this study, we used MEIRS to study the dynamic response of live cancer cells to a newly developed chemotherapeutic metal complex with distinct modes of action (MoAs): tricarbonyl rhenium isonitrile polypyridyl (TRIP). MEIRS measurements demonstrated that administering TRIP resulted in long-term (several hours) reduction in protein, lipid, and overall refractive index signals, and in short-term (tens of minutes) increase in these signals, consistent with the induction of endoplasmic reticulum stress. The unique tricarbonyl IR signature of TRIP in the bioorthogonal spectral window was monitored in real time, and was used as an infrared tag to detect the precise drug delivery time that was shown to be closely correlated with the onset of the phenotypic response. These results demonstrate that MEIRS is an effective label-free real-time cellular assay capable of detecting and interpreting the early phenotypic responses of cells to IR-tagged chemotherapeutics. 

Abstract Inhibitors of the mitochondrial calcium uniporter (MCU) are valuable tools for studying the role of mitochondrial Ca²⁺in various pathophysiological conditions. In this study, a new fluorogenic MCU inhibitor,RuOCou, is presented. This compound is an analogue of the known MCU inhibitor Ru265 that contains fluorescent axial coumarin carboxylate ligands. Upon aquation ofRuOCouand release of the axial coumarin ligands, a simultaneous increase in its MCU‐inhibitory activity and fluorescence intensity is observed. The fluorescence response of this compound enabled its aquation to be monitored in both HeLa cell lysates and live HeLa cells. This fluorogenic prodrug represents a potential theranostic MCU inhibitor that can be leveraged for the treatment of human diseases related to MCU activity.