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, Madesh Muniswamy

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Mitochondrial Ca2+ (mCa2+) 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 Ca2+ dynamics and mitochondrial membrane potential (Δm). 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)
JournalACS Central Science
DOIs
StateAccepted/In press - Jan 1 2019

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

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

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.; Muniswamy, Madesh.

In: ACS Central Science, 01.01.2019.

Research output: Contribution to journalArticle

Woods, JJ, Nemani, N, Shanmughapriya, S, Kumar, A, Zhang, M, Nathan, SR, Thomas, M, Carvalho, E, Ramachandran, K, Srikantan, S, Stathopulos, PB, Wilson, JJ & Muniswamy, M 2019, 'A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury', ACS Central Science. https://doi.org/10.1021/acscentsci.8b00773
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. ; Muniswamy, Madesh. / A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury. In: ACS Central Science. 2019.
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