Mitochondrial Ca²⁺ uptake has long been considered crucial for meeting the fluctuating energy demands of cells in the heart and other tissues. Increases in mitochondrial matrix [Ca²⁺] drive mitochondrial ATP production via stimulation of Ca²⁺-sensitive dehydrogenases. Mitochondria-targeted sensors have revealed mitochondrial matrix [Ca²⁺] rises that closely follow the cytoplasmic [Ca²⁺] signals in many paradigms. Mitochondrial Ca²⁺ uptake is mediated by the Ca²⁺ uniporter (mtCU). Pharmacological manipulation of the mtCU is potentially key to understanding its physiological significance, but no specific, cell-permeable inhibitors were identified. In the past decade, as the molecular identity of the mtCU was brought to light, efforts have focused on genetic targeting. However, in the cells/animals that are able to survive impaired mtCU function, robust compensatory changes were found in the mtCU as well as other mechanisms. Thus, the discovery, through chemical library screens on normal and mtCU-deficient cells, of new small-molecule inhibitors with improved cell permeability and specificity might offer a better chance to test the relevance of mitochondrial Ca²⁺ uptake. Success with the development of small molecule mtCU inhibitors is also expected to have clinical impact, considering the growing evidence for the role of mitochondrial Ca²⁺ uptake in a variety of diseases, including heart attack, stroke and various neurodegenerative disorders. Here, we review the progress in pharmacological targeting of mtCU and illustrate the challenges in this field using data obtained with MCU-i11, a new small molecule inhibitor.

长期以来，线粒体 Ca ²⁺吸收一直被认为对于满足心脏和其他组织细胞波动的能量需求至关重要。线粒体基质 [Ca ^{2+ ] 的增加通过刺激 Ca 2+}敏感脱氢酶驱动线粒体 ATP 产生。线粒体靶向传感器显示，在许多范例中，线粒体基质 [Ca ²⁺ ] 的上升密切遵循细胞质 [Ca ^{2+ ] 信号。}线粒体 Ca ²⁺摄取由 Ca ²⁺单向转运蛋白 (mtCU) 介导。mtCU 的药理学操作可能是理解其生理意义的关键，但尚未发现特异性的细胞渗透性抑制剂。在过去的十年中，随着 mtCU 的分子身份被曝光，人们的努力集中在基因靶向上。然而，在能够在 mtCU 功能受损的细胞/动物中存活下来，在 mtCU 以及其他机制中发现了强有力的代偿性变化。因此，通过对正常细胞和 mtCU 缺陷细胞进行化学库筛选，发现具有改善的细胞通透性和特异性的新型小分子抑制剂，可能为测试线粒体 Ca 2+ 吸收的相关性提供更好的^机会。^{考虑到越来越多的证据表明线粒体 Ca 2+}摄取在多种疾病（包括心脏病、中风和各种神经退行性疾病）中的作用，小分子 mtCU 抑制剂的成功开发预计也会产生临床影响。在这里，我们回顾了 mtCU 药理学靶向的进展，并利用新型小分子抑制剂 MCU-i11 获得的数据说明了该领域面临的挑战。