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Title: A [ 1 H, 15 N] Heteronuclear Single Quantum Coherence NMR Study of the Solution Reactivity of the Ruthenium‐Based Mitochondrial Calcium Uniporter Inhibitor Ru265
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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Award ID(s):
1750295
NSF-PAR ID:
10369258
Author(s) / Creator(s):
 ;  ;  
Publisher / Repository:
Wiley Blackwell (John Wiley & Sons)
Date Published:
Journal Name:
European Journal of Inorganic Chemistry
Volume:
2022
Issue:
6
ISSN:
1434-1948
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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    Excitotoxicity due to mitochondrial calcium (Ca2+) overloading can trigger neuronal cell death in a variety of pathologies. Inhibiting the mitochondrial calcium uniporter (MCU) has been proposed as a therapeutic avenue to prevent calcium overloading. Ru265 (ClRu(NH3)4(μ‐N)Ru(NH3)4Cl]Cl3) is a cell‐permeable inhibitor of the mitochondrial calcium uniporter (MCU) with nanomolar affinity. Ru265 reduces sensorimotor deficits and neuronal death in models of ischemic stroke. However, the therapeutic use of Ru265 is limited by the induction of seizure‐like behaviours.

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    We examined the effect of Ru265 on synaptic and neuronal function in acute brain slices and hippocampal neuron cultures derived from mice, in control and where MCU expression was genetically abrogated.

    Key Results

    Ru265 decreased evoked responses from calyx terminals and induced spontaneous action potential firing of both the terminal and postsynaptic principal cell. Recordings of presynaptic Ca2+currents suggested that Ru265 blocks the P/Q type channel, confirmed by the inhibition of currents in cells exogenously expressing the P/Q type channel. Measurements of presynaptic K+currents further revealed that Ru265 blocked a KCNQ current, leading to increased membrane excitability, underlying spontaneous spiking. Ca2+imaging of hippocampal neurons showed that Ru265 increased synchronized, high‐amplitude events, recapitulating seizure‐like activity seenin vivo. Importantly, MCU ablation did not suppress Ru265‐induced increases in neuronal activity and seizures.

    Conclusions and Implications

    Our findings provide a mechanistic explanation for the pro‐convulsant effects of Ru265 and suggest counter screening assays based on the measurement of P/Q and KCNQ channel currents to identify safe MCU inhibitors.

     
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