TY - JOUR
T1 - A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury
AU - Woods, Joshua J.
AU - Nemani, Neeharika
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
N1 - Publisher Copyright:
© 2019 American Chemical Society.
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.
UR - https://www.scopus.com/pages/publications/85059762454
UR - https://www.scopus.com/pages/publications/85059762454#tab=citedBy
U2 - 10.1021/acscentsci.8b00773
DO - 10.1021/acscentsci.8b00773
M3 - Article
AN - SCOPUS:85059762454
SN - 2374-7943
VL - 5
SP - 153
EP - 166
JO - ACS Central Science
JF - ACS Central Science
IS - 1
ER -