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Abstract The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca2+) into the mitochondria, a process that is vital for maintaining normal cellular function. Inhibitors of the MCU, the most promising of which are dinuclear ruthenium coordination compounds, have found use as both therapeutic agents and tools for studying the importance of this ion channel. In this study, six Co3+cage compounds with sarcophagine‐like ligands were assessed for their abilities to inhibit MCU‐mediated mitochondrial Ca2+uptake. These complexes were synthesized and characterized according to literature procedures and then investigated in cellular systems for their MCU‐inhibitory activities. Among these six compounds, [Co(sen)]3+(3, sen=5‐(4‐amino‐2‐azabutyl)‐5‐methyl‐3,7‐diaza‐1,9‐nonanediamine) was identified to be a potent MCU inhibitor, with IC50values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound3was determined, revealing moderate accumulation in cells. Most notably,3was demonstrated to operate in intact cells as an MCU inhibitor. Collectively, this work presents the viability of using cobalt coordination complexes as MCU inhibitors, providing a new direction for researchers to investigate.
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A Fluorogenic Inhibitor of the Mitochondrial Calcium Uniporter
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.
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- Award ID(s):
- 1750295
- PAR ID:
- 10390446
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 62
- Issue:
- 6
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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