Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)
Abstract
Abstract The mitochondrial calcium uniporter (MCU) is the ion channel that mediates Ca 2+ uptake in mitochondria. Inhibitors of the MCU are valuable as potential therapeutic agents and tools to study mitochondrial Ca 2+ . The best‐known inhibitor of the MCU is the ruthenium compound Ru360. Although this compound is effective in permeabilized cells, it does not work in intact biological systems. We have recently reported the synthesis and characterization of Ru265, a complex that selectively inhibits the MCU in intact cells. Here, the physical and biological properties of Ru265 and Ru360 are described in detail. Using atomic absorption spectroscopy and X‐ray fluorescence imaging, we show that Ru265 is transported by organic cation transporter 3 (OCT3) and taken up more effectively than Ru360. As an explanation for the poor cell uptake of Ru360, we show that Ru360 is deactivated by biological reductants. These data highlight how structural modifications in metal complexes can have profound effects on their biological activities.
- Authors:
-
[1];
[3];
[2];
[4]
- Department of Chemistry and Chemical Biology Cornell University Ithaca NY 14853 USA, Robert F. Smith School for Chemical and Biomolecular Engineering Cornell University Ithaca NY 14853 USA
- Department of Chemistry The University of Adelaide Adelaide SA 5005 Australia
- Advanced Photon Source X-ray Science Division Argonne National Laboratory Argonne IL 60439 USA
- Department of Chemistry and Chemical Biology Cornell University Ithaca NY 14853 USA
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1604097
- Resource Type:
- Publisher's Accepted Manuscript
- Journal Name:
- Angewandte Chemie
- Additional Journal Information:
- Journal Name: Angewandte Chemie Journal Volume: 132 Journal Issue: 16; Journal ID: ISSN 0044-8249
- Publisher:
- Wiley Blackwell (John Wiley & Sons)
- Country of Publication:
- Germany
- Language:
- English
Citation Formats
Woods, Joshua J., Lovett, James, Lai, Barry, Harris, Hugh H., and Wilson, Justin J. Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU). Germany: N. p., 2020.
Web. doi:10.1002/ange.202000247.
Woods, Joshua J., Lovett, James, Lai, Barry, Harris, Hugh H., & Wilson, Justin J. Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU). Germany. https://doi.org/10.1002/ange.202000247
Woods, Joshua J., Lovett, James, Lai, Barry, Harris, Hugh H., and Wilson, Justin J. Tue .
"Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)". Germany. https://doi.org/10.1002/ange.202000247.
@article{osti_1604097,
title = {Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)},
author = {Woods, Joshua J. and Lovett, James and Lai, Barry and Harris, Hugh H. and Wilson, Justin J.},
abstractNote = {Abstract The mitochondrial calcium uniporter (MCU) is the ion channel that mediates Ca 2+ uptake in mitochondria. Inhibitors of the MCU are valuable as potential therapeutic agents and tools to study mitochondrial Ca 2+ . The best‐known inhibitor of the MCU is the ruthenium compound Ru360. Although this compound is effective in permeabilized cells, it does not work in intact biological systems. We have recently reported the synthesis and characterization of Ru265, a complex that selectively inhibits the MCU in intact cells. Here, the physical and biological properties of Ru265 and Ru360 are described in detail. Using atomic absorption spectroscopy and X‐ray fluorescence imaging, we show that Ru265 is transported by organic cation transporter 3 (OCT3) and taken up more effectively than Ru360. As an explanation for the poor cell uptake of Ru360, we show that Ru360 is deactivated by biological reductants. These data highlight how structural modifications in metal complexes can have profound effects on their biological activities.},
doi = {10.1002/ange.202000247},
journal = {Angewandte Chemie},
number = 16,
volume = 132,
place = {Germany},
year = {Tue Mar 10 00:00:00 EDT 2020},
month = {Tue Mar 10 00:00:00 EDT 2020}
}
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