一种具有选择性且可穿透细胞的线粒体钙单向转运体（MCU）抑制剂在缺氧/复氧损伤后可维持线粒体生物能量学。
A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury.
作者信息
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
机构信息
Robert F. Smith School for Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, United States.
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
出版信息
ACS Cent Sci. 2019 Jan 23;5(1):153-166. doi: 10.1021/acscentsci.8b00773. Epub 2019 Jan 4.
Mitochondrial Ca (Ca) 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 dynamics and mitochondrial membrane potential (ΔΨ). 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.
由线粒体钙单向转运体（MCU）介导的线粒体钙（Ca）摄取在信号转导、生物能量学和细胞死亡中起着关键作用，其失调与多种人类疾病相关。在本研究中，我们报道了一种新的钌配合物Ru265，它具有细胞通透性、低毒性且对MCU抑制作用高效。用Ru265处理的细胞显示MCU活性受到抑制，而对胞质钙动力学和线粒体膜电位（ΔΨ）没有任何影响。剂量依赖性研究表明，Ru265比目前使用的MCU抑制剂Ru360更有效。人MCU N端结构域中Cys97的定点诱变消除了Ru265的抑制活性，表明这个位于基质的结构域是其作用靶点。此外，Ru265预防了缺氧/复氧损伤及随后的线粒体功能障碍，表明这种新抑制剂是研究MCU在完整生物学模型中功能作用的有价值工具。
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