Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)

Woods Joshua J.; Lovett James; Lai Barry; Harris Hugh H.; Wilson Justin J.

摘要

Abstract > The mitochondrial calcium uniporter (MCU) is the ion channel that mediates Ca 2+ uptake in mitochondria. Inhibitors of the MCU are valuable as potential therapeutic agents and tools to study mitochondrial Ca 2+ . The best‐known inhibitor of the MCU is the ruthenium compound Ru360. Although this compound is effective in permeabilized cells, it does not work in intact biological systems. We have recently reported the synthesis and characterization of Ru265, a complex that selectively inhibits the MCU in intact cells. Here, the physical and biological properties of Ru265 and Ru360 are described in detail. Using atomic absorption spectroscopy and X‐ray fluorescence imaging, we show that Ru265 is transported by organic cation transporter 3 (OCT3) and taken up more effectively than Ru360. As an explanation for the poor cell uptake of Ru360, we show that Ru360 is deactivated by biological reductants. These data highlight how structural modifications in metal complexes can have profound effects on their biological activities. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“Main”XML：Lang =“en”> <标题类型=“main”>抽象</ title> > 线粒体钙钙（MCU）是介导CA的离子通道 2 + </ sup> 在线粒体摄取。 MCU的抑制剂是有价值的潜在治疗剂和研究线粒体CA的工具 2 + </ sup> 。 MCU的最着名的抑制剂是钌化合物RU360。虽然该化合物在透明细胞中有效，但它不适用于完整的生物系统。我们最近报道了Ru265的合成和表征，一种复合物，其在完整细胞中选择性地抑制MCU。这里，详细描述Ru265和Ru360的物理和生物学性质。使用原子吸收光谱和X射线荧光成像，我们表明RU265由有机阳离子转运蛋白3（OCT3）运输并比RU360更有效地溶解。作为对Ru360的差的细胞摄取的解释，我们表明Ru360因生物学还原剂而被激活。这些数据突出了金属配合物的结构修改如何对其生物活动产生深远的影响。 </ p> </摘要> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-19011/'>《Angewandte Chemie》</a> <b style="margin: 0 2px;">|</b><span>2020年第16期</span><b style="margin: 0 2px;">|</b><span>共10页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Woods Joshua J.&option=202" target="_blank" rel="nofollow">Woods Joshua J.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Lovett James&option=202" target="_blank" rel="nofollow">Lovett James;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Lai Barry&option=202" target="_blank" rel="nofollow">Lai Barry;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Harris Hugh H.&option=202" target="_blank" rel="nofollow">Harris Hugh H.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wilson Justin J.&option=202" target="_blank" rel="nofollow">Wilson Justin J.;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of Chemistry and Chemical BiologyCornell UniversityIthaca NY 14853 USA;</p> <p>Department of ChemistryThe University of AdelaideAdelaide SA 5005 Australia;</p> <p>Advanced Photon SourceArgonne National LaboratoryArgonne IL 60439 USA;</p> <p>Department of ChemistryThe University of AdelaideAdelaide SA 5005 Australia;</p> <p>Department of Chemistry and Chemical BiologyCornell UniversityIthaca NY 14853 USA;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/1188.html" title="应用化学">应用化学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=bioinorganic chemistry&option=203" rel="nofollow">bioinorganic chemistry;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=mitochondrial calcium uniporter&option=203" rel="nofollow">mitochondrial calcium uniporter;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=organic cation transporter&option=203" rel="nofollow">organic cation transporter;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=ruthenium&option=203" rel="nofollow">ruthenium;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=X-ray fluorescence imaging&option=203" rel="nofollow">X-ray fluorescence imaging;</a> </p> <div class="translation"> 机译：生物碳化物化学;线粒体钙百钙;有机阳离子转运蛋白;钌;X射线荧光成像; 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