A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury

Joshua J. Woods; Neeharika Nemani; Santhanam Shanmughapriya; Akshay Kumar; Mengqi Zhang; Sarah R. Nathan; Manfred Thomas; Edmund Carvalho; Karthik Ramachandran; Subramanya Srikantan; Peter B. Stathopulos; Justin J. Wilson; Muniswamy Madesh

doi:10.1021/acscentsci.8b00773

A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury

Joshua J. Woods
, Neeharika Nemani
, Santhanam Shanmughapriya
, Akshay Kumar
, Mengqi Zhang
, Sarah R. Nathan
, Manfred Thomas
, Edmund Carvalho
, Karthik Ramachandran
, Subramanya Srikantan
, Peter B. Stathopulos
, Justin J. Wilson
, Muniswamy Madesh

Department of Medicine

Research output: Contribution to journal › Article › peer-review

144 Scopus citations

Abstract

Mitochondrial Ca ²⁺ ( _m Ca ²⁺ ) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca ²⁺ dynamics and mitochondrial membrane potential ( _m ). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.

Original language	English (US)
Pages (from-to)	153-166
Number of pages	14
Journal	ACS Central Science
Volume	5
Issue number	1
DOIs	https://doi.org/10.1021/acscentsci.8b00773
State	Published - Jan 23 2019

All Science Journal Classification (ASJC) codes

General Chemistry
General Chemical Engineering

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10.1021/acscentsci.8b00773

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Woods, J. J., Nemani, N., Shanmughapriya, S., Kumar, A., Zhang, M., Nathan, S. R., Thomas, M., Carvalho, E., Ramachandran, K., Srikantan, S., Stathopulos, P. B., Wilson, J. J., & Madesh, M. (2019). A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury. ACS Central Science, 5(1), 153-166. https://doi.org/10.1021/acscentsci.8b00773

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title = "A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury",

abstract = " Mitochondrial Ca 2+ ( m Ca 2+ ) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca 2+ dynamics and mitochondrial membrane potential ( m ). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.",

author = "Woods, \{Joshua J.\} and Neeharika Nemani and Santhanam Shanmughapriya and Akshay Kumar and Mengqi Zhang and Nathan, \{Sarah R.\} and Manfred Thomas and Edmund Carvalho and Karthik Ramachandran and Subramanya Srikantan and Stathopulos, \{Peter B.\} and Wilson, \{Justin J.\} and Muniswamy Madesh",

note = "Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = jan,

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doi = "10.1021/acscentsci.8b00773",

language = "English (US)",

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Woods, JJ, Nemani, N, Shanmughapriya, S, Kumar, A, Zhang, M, Nathan, SR, Thomas, M, Carvalho, E, Ramachandran, K, Srikantan, S, Stathopulos, PB, Wilson, JJ & Madesh, M 2019, 'A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury', ACS Central Science, vol. 5, no. 1, pp. 153-166. https://doi.org/10.1021/acscentsci.8b00773

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AU - Shanmughapriya, Santhanam

AU - Kumar, Akshay

AU - Zhang, Mengqi

AU - Nathan, Sarah R.

AU - Thomas, Manfred

AU - Carvalho, Edmund

AU - Ramachandran, Karthik

AU - Srikantan, Subramanya

AU - Stathopulos, Peter B.

AU - Wilson, Justin J.

AU - Madesh, Muniswamy

PY - 2019/1/23

Y1 - 2019/1/23

N2 - Mitochondrial Ca 2+ ( m Ca 2+ ) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca 2+ dynamics and mitochondrial membrane potential ( m ). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.

AB - Mitochondrial Ca 2+ ( m Ca 2+ ) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca 2+ dynamics and mitochondrial membrane potential ( m ). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.

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A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury

Abstract

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