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

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.

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis

“…Nevertheless, POMCOpa1KO mice preserved the ability to dynamically increase cytosolic Ca 2+ (detected via AAV-GCamP7s) upon food presentation confirming a mitochondria-specific Ca 2+ handling defect ( Figure 6 C). MCU inhibition with the selective and cell-permeable Ru265 compound ( Woods and Wilson, 2020 ; Woods et al., 2019 , 2020 ) blocked mitochondrial Ca 2+ uptake in control mice ( Figures 6 D and 6E), confirming the specificity and accurate performance of the mtGCaMP6s reporter. Remarkably, MCU inhibition restored the mitochondrial Ca 2+ dynamics in mutant mice ( Figures 6 D and 6E).…”

A [1H,15N] Heteronuclear Single Quantum Coherence NMR Study of the Solution Reactivity of the Ruthenium‐Based Mitochondrial Calcium Uniporter Inhibitor Ru265

“…Although we have previously studied the aquation of Ru265 by UV‐vis spectroscopy, [29] the direct observation of [ClRu( 15 NH 3 ) 4 (μ‐N)Ru( 15 NH 3 ) 4 (OH 2 )] 4+ by [ 1 H, 15 N] HSQC NMR spectroscopy prompted us to reinvestigate this process. With our prior studies, only a single pseudo‐first‐order rate constant was determined even though the loss of the two chlorido ligands occurs through a step‐wise process (Figure 2a).…”

Metal complexes for therapeutic applications

“…Capitalizing on these advantages, a variety of metal-containing compounds have already been clinically approved for a wide range of therapeutic applications. Increasing efforts to not only identify bioactive metal complexes [41] but deeply understand their mechanism of action [87][88][89][90] will be an important next step in their advancement and greater acceptance in the medical community (see Outstanding questions). Further investigation into the therapeutic applications of metal complexes will yield novel compounds with increased potency and selectivity and may even lead to the discovery of entirely new therapeutic strategies.…”