Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)

Woods, Joshua J.; Lovett, James; Lai, Barry; Harris, Hugh H.; Wilson, Justin J.

doi:10.1002/ange.202000247

Title: Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)

Journal Article · 10 March 2020 · Angewandte Chemie

DOI: https://doi.org/10.1002/ange.202000247 · OSTI ID:1604097

^[1]; Lovett, James ^[2];

^[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

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.

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Sponsoring Organization:: USDOE

OSTI ID:: 1604097

Journal Information:: Angewandte Chemie, Journal Name: Angewandte Chemie Vol. 132 Journal Issue: 16; ISSN 0044-8249

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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