The mitochondrial calcium uniporter (MCU) is a transmembrane protein that resides on the inner membrane of the mitochondria and mediates calcium uptake into this organelle. Given the critical role of mitochondrial calcium trafficking in cellular function, inhibitors of this channel have arisen as tools for studying the biological relevance of this process and as potential therapeutic agents. In this study, four new analogues of the previously reported Ru-based MCU inhibitor [ClRu(NH 3 ) 4 (μ-N)Ru(NH 3 ) 4 Cl]Cl 3 (Ru265) are reported. These compounds, which bear axial carboxylate ligands, are of the general formula [(RCO 2 )Ru(NH 3 ) 4 (μ-N)Ru(NH 3 ) 4 (O 2 CR)]X 3 , where X = NO 3 − or CF 3 SO 3 − and R = H (1), CH 3 (2), CH 2 CH 3 (3), and (CH 2 ) 2 CH 3 (4). These complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis. X-ray crystal structures of 1 and 3 were obtained, revealing the expected presence of both the linear Ru(μ-N)Ru core and axial formate and propionate ligands. The axial carboxylate ligands of complexes 1− 4 are displaced by water in buffered aqueous solution to give the aquated compound Ru265′. The kinetics of these processes were measured by 1 H NMR spectroscopy, revealing half-lives that span 5.9−9.9 h at 37 °C. Complex 1 with axial formate ligands underwent aquation approximately twice as fast as the other compounds. In vitro cytotoxicity and mitochondrial membrane potential measurements carried out in HeLa and HEK293T cells demonstrated that none of these four complexes negatively affects cell viability or mitochondrial function. The abilities of 1−4 to inhibit mitochondrial calcium uptake in permeabilized HEK293T cells were assessed and compared to that of Ru265. Fresh solutions of 1−4 are approximately 2-fold less potent than Ru265 with IC 50 values in the range of 14.7−19.1 nM. Preincubating 1−4 in aqueous buffers for longer time periods to allow for the aquation reactions to proceed increases their potency of mitochondrial uptake inhibition to match that of Ru265. This result indicates that 1− 4 are aquation-activated prodrugs of Ru265′. Finally, 1−4 were shown to inhibit mitochondrial calcium uptake in intact, nonpermeabilized cells, revealing their value as tools and potential therapeutic agents for mitochondrial calcium-related disorders.

We have investigated the biological properties of the osmium analogue of a potent ruthenium-based mitochondrial calcium uniporter inhibitor and have found it to possess distinct properties.

Ischemia-reperfusion injury (IRI), which describes the cell damage and death that occurs after blood and oxygen are restored to ischemic or hypoxic tissue, is a significant factor within the mortality rates of heart disease and stroke patients. At the cellular level, the return of oxygen triggers an increase in reactive oxygen species (ROS) and mitochondrial calcium ( m Ca 2+ ) overload, which both contribute to cell death. Despite the widespread occurrence of IRI in different pathological conditions, there are currently no clinically approved therapeutic agents for its management. In this Perspective, we will briefly discuss the current therapeutic options for IRI and then describe in great detail the potential role and arising applications of metal-containing coordination and organometallic complexes for treating this condition. This Perspective categorizes these metal compounds based on their mechanisms of action, which include their use as delivery agents for gasotransmitters, inhibitors of m Ca 2+ uptake, and catalysts for the decomposition of ROS. Lastly, the challenges and opportunities for inorganic chemistry approaches to manage IRI are discussed.

The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca 2 + ) into the mitochondria, a process that is vital for maintaining normal cellular function. Inhibitors of the MCU, the most promising of which are dinuclear ruthenium coordination compounds, have found use as both therapeutic agents and tools for studying the importance of this ion channel. In this study, six Co 3 + cage compounds with sarcophagine-like ligands were assessed for their abilities to inhibit MCU-mediated mitochondrial Ca 2 + uptake. These complexes were synthesized and characterized according to literature procedures and then investigated in cellular systems for their MCU-inhibitory activities. Among these six compounds, [Co(sen)] 3 + (3, sen = 5-(4-amino-2-azabutyl)-5-methyl-3,7-diaza-1,9-nonanediamine) was identified to be a potent MCU inhibitor, with IC 50 values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound 3 was determined, revealing moderate accumulation in cells. Most notably, 3 was demonstrated to operate in intact cells as an MCU inhibitor. Collectively, this work presents the viability of using cobalt coordination complexes as MCU inhibitors, providing a new direction for researchers to investigate.

There currently exists a significant deficiency in the nuclear chemistry workforce within the United States, despite its importance in areas of medicine, national security, and energy. Poor coverage of this topic across many chemistry departments at the undergraduate level likely contributes to this shortage. Increasing interest and hands-on experience through the availability of laboratory experiments may help alleviate this burden. Herein, we describe a set of nuclear chemistry experiments designed for undergraduate students that can be readily implemented in chemistry departments without specialized programs in this area. These experiments emphasize several concepts related to safe work practices with radioactive materials, such as the effects of distance and shielding. Additionally, the use of a commercially available radionuclide generator was implemented to have students identify an "unknown" radionuclide based on its measured half-life and gamma (γ) spectrum. This laboratory experiment was carried out by two chemistry courses at Cornell University. Student feedback obtained from these sections showed that this hands-on experiment enhanced student understanding of several key concepts of nuclear chemistry and also successfully stimulated interest in this topic. Therefore, this study demonstrates that simple nuclear chemistry laboratory experiments can be implemented in a diverse range of chemistry departments and are effective at fostering student understanding and interest in this topic.