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  1. Abstract

    The mitochondrial calcium uniporter (MCU) is a transmembrane protein that is responsible for mediating mitochondrial calcium (mCa2+) uptake. Given this critical function, the MCU has been implicated as an important target for addressing various human diseases. As such, there has a been growing interest in developing small molecules that can inhibit this protein. To date, metal coordination complexes, particularly multinuclear ruthenium complexes, are the most widely investigated MCU inhibitors due to both their potent inhibitory activities as well as their longstanding use for this application. Recent efforts have expanded the metal‐based toolkit for MCU inhibition. This concept paper summarizes the development of new metal‐based inhibitors of the MCU and their structure‐activity relationships in the context of improving their potential for therapeutic use in managing human diseases related tomCa2+dysregulation.

     
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    Free, publicly-accessible full text available June 15, 2024
  2. Abstract

    The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca2+) 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 Co3+cage compounds with sarcophagine‐like ligands were assessed for their abilities to inhibit MCU‐mediated mitochondrial Ca2+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 IC50values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound3was determined, revealing moderate accumulation in cells. Most notably,3was 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.

     
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  3. Abstract

    Inhibitors of the mitochondrial calcium uniporter (MCU) are valuable tools for studying the role of mitochondrial Ca2+in various pathophysiological conditions. In this study, a new fluorogenic MCU inhibitor,RuOCou, is presented. This compound is an analogue of the known MCU inhibitor Ru265 that contains fluorescent axial coumarin carboxylate ligands. Upon aquation ofRuOCouand release of the axial coumarin ligands, a simultaneous increase in its MCU‐inhibitory activity and fluorescence intensity is observed. The fluorescence response of this compound enabled its aquation to be monitored in both HeLa cell lysates and live HeLa cells. This fluorogenic prodrug represents a potential theranostic MCU inhibitor that can be leveraged for the treatment of human diseases related to MCU activity.

     
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  4. Abstract

    The synthesis and characterization of the15N‐labeled analogue of the mitochondrial calcium uptake inhibitor [Cl(NH3)4Ru(μ‐N)Ru(NH3)4Cl]3+(Ru265) bearing [15N]NH3ligands is reported. Using [1H,15N] HSQC NMR spectroscopy, the rate constants for the axial chlorido ligand aquation of [15N]Ru265 in pH 7.4 buffer at 25 °C were found to bek1=(3.43±0.03)×10−4 s−1andk2=(4.03±0.09)×10−3 s−1. The reactivity of [15N]Ru265 towards biologically relevant small molecules was also assessed via this method, revealing that this complex can form coordination bonds to anionic oxygen and sulfur donors. Time‐based studies on these ligand‐binding reactions reveal this process to be slow relative to the time required for the complex to inhibit mitochondrial calcium uptake, suggesting that hydrogen‐bonding interactions, rather than the formation of coordination bonds, may play a more significant role in mediating the inhibitory properties of this complex.

     
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  5. Abstract

    Hydrogen sulfide (H2S) is a gaseous molecule that has received attention for its role in biological processes and therapeutic potential in diseases, such as ischemic reperfusion injury. Despite its clinical relevance, delivery of H2S to biological systems is hampered by its toxicity at high concentrations. Herein, we report the first metal‐based H2S donor that delivers this gas selectively to hypoxic cells. We further show that H2S release from this compound protects H9c2 rat cardiomyoblasts from an in vitro model of ischemic reperfusion injury. These results validate the utility of redox‐activated metal complexes as hypoxia‐selective H2S‐releasing agents for use as tools to study the role of this gaseous molecule in complex biological systems.

     
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  6. Abstract

    The mitochondrial calcium uniporter (MCU) is the ion channel that mediates Ca2+uptake in mitochondria. Inhibitors of the MCU are valuable as potential therapeutic agents and tools to study mitochondrial Ca2+. 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.

     
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  7. 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 (mCa2+) 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 mCa2+ uptake, and catalysts for the decomposition of ROS. Lastly, the challenges and opportunities for inorganic chemistry approaches to manage IRI are discussed. 
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  8. An analogue of the mitochondrial calcium uniporter (MCU) inhibitor Ru265 containing axial ferrocenecarboxylate ligands is reported. This new complex exhibits enhanced cellular uptake compared to the parent compound Ru265.

     
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  9. 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.

     
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