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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)153-166
Number of pages14
JournalACS Central Science
Volume5
Issue number1
DOIs
StatePublished - Jan 23 2019

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Calcium
Signal transduction
Mutagenesis
Ruthenium
Poisons
Cell death
Energy Metabolism
mitochondrial calcium uniporter
Membranes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Woods, Joshua J. ; Nemani, Neeharika ; Shanmughapriya, Santhanam ; Kumar, Akshay ; Zhang, Mengqi ; Nathan, Sarah R. ; Thomas, Manfred ; Carvalho, Edmund ; Ramachandran, Karthik ; Srikantan, Subramanya ; Stathopulos, Peter B. ; Wilson, Justin J. ; Madesh, Muniswamy. / A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury. In: ACS Central Science. 2019 ; Vol. 5, No. 1. pp. 153-166.
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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.",
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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

A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury. / Woods, Joshua J.; Nemani, Neeharika; Shanmughapriya, Santhanam; Kumar, Akshay; Zhang, Mengqi; Nathan, Sarah R.; Thomas, Manfred; Carvalho, Edmund; Ramachandran, Karthik; Srikantan, Subramanya; Stathopulos, Peter B.; Wilson, Justin J.; Madesh, Muniswamy.

In: ACS Central Science, Vol. 5, No. 1, 23.01.2019, p. 153-166.

Research output: Contribution to journalArticle

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AU - Ramachandran, Karthik

AU - Srikantan, Subramanya

AU - Stathopulos, Peter B.

AU - Wilson, Justin J.

AU - Madesh, Muniswamy

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