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

被引：127

作者：

Woods, Joshua J. ^{[1
,2
]}

Nemani, Neeharika ^{[3
,4
]}

Shanmughapriya, Santhanam ^{[3
,4
]}

Kumar, Akshay ^{[3
,4
]}

Zhang, MengQi ^{[5
]}

Nathan, Sarah R. ^{[2
]}

Thomas, Manfred ^{[3
,4
]}

Carvalho, Edmund ^{[3
,4
]}

Ramachandran, Karthik ^{[6
]}

Srikantan, Subramanya ^{[6
]}

Stathopulos, Peter B. ^{[5
]}

Wilson, Justin J. ^{[2
]}

Madesh, Muniswamy ^{[3
,4
,6
]}

机构：

[1] Cornell Univ, Robert F Smith Sch Chem & Biomol Engn, Ithaca, NY 14853 USA

[2] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA

[3] Temple Univ, Lewis Katz Sch Med, Dept Med Genet & Mol Biochem, Philadelphia, PA 19140 USA

[4] Temple Univ, Lewis Katz Sch Med, Ctr Translat Med, Philadelphia, PA 19140 USA

[5] Western Univ, Dept Physiol & Pharmacol, London, ON N6A 5C1, Canada

[6] Univ Texas Hlth San Antonio, Inst Precis Med & Hlth, Dept Med Nephrol, San Antonio, TX 78229 USA

来源：

ACS CENTRAL SCIENCE | 2019年 / 5卷 / 01期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

CA2+ UNIPORTER; RUTHENIUM COMPLEXES; ESSENTIAL COMPONENT; BIOLOGICAL-ACTIVITY; NITRIDO-COMPLEXES; INDUCED APOPTOSIS; TOPOISOMERASE-II; POTENT INHIBITOR; ARENE COMPLEXES; ION TRANSPORT;

D O I：

10.1021/acscentsci.8b00773

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Mitochondrial Ca2+ (Ca-m(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 Ca2+ dynamics and mitochondrial membrane potential (Delta Psi(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.

引用

页码：153 / 166

页数：14

共 94 条

[1] Hydrogen peroxide-mediated cytosolic acidification is a signal for mitochondrial translocation of Bax during drug-induced apoptosis of tumor cells [J].