Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models

Schweitzer, Maria K.; Wilting, Fabiola; Sedej, Simon; Dreizehnter, Lisa; Dupper, Nathan J.; Tian, Qi; Moretti, Alessandra; My, Ilaria; Kwon, Ohyun; Priori, Silvia G.; Laugwitz, Karl‐Ludwig; Storch, Ursula; Lipp, Peter; Breit, Andreas; Schnitzler, Michael Mederos y; Gudermann, Thomas; Schredelseker, Johann

doi:10.1016/j.jacbts.2017.06.008

Cited by 40 publications

(69 citation statements)

References 45 publications

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“…In this study, we present evidence that the efsevin‐induced change in gating facilitates transfer of Ca 2+ from the SR into mitochondria. Interestingly, we never observed an involvement of the drug in apoptosis, neither in this study nor in previous studies (Schweitzer et al, 2017; Shimizu et al, 2015) despite a previously identified isoform‐specific role for VDAC2 in apoptosis through recruitment of Bax (Lauterwasser et al, 2016; Ma et al, 2014). Efsevin could thus serve as a tool to dissect these functions in future studies.…”

Section: Discussioncontrasting

confidence: 92%

“…It is thus conceivable that despite the ubiquitous expression of VDACs in the body, efsevin‐mediated effects are most pronounced or even limited to cardiomyocytes due to the specialized role of VDAC2 in this tissue. This effect might also explain the lack of major side effects that were observed previously in translational models (Schweitzer et al, 2017). However, future studies are needed to evaluate the role of the efsevin‐mediated effects on other VDAC2‐mediated effects like apoptosis or regulation of bioenergetics (for a review, see Naghdi & Hajnóczky, 2016).…”

Section: Discussionmentioning

confidence: 52%

“…Fluorescence‐based measurements of mitochondrial Ca 2+ were performed as previously described (Schweitzer et al, 2017). In brief, HL‐1 cells () were plated in 96‐well plates 1 day prior to the experiment.…”

Section: Methodsmentioning

confidence: 99%

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The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca²⁺ uptake

Wilting¹,

Kopp²,

Gurnev

et al. 2020

British J Pharmacology

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Background and Purpose: The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane.Here, we investigated the molecular mechanism of the efsevin-VDAC2 interaction.Experimental Approach: To evaluate the functional interaction of efsevin and VDAC2, we measured currents through recombinant VDAC2 in planar lipid bilayers.Using molecular ligand-protein docking and mutational analysis, we identified the efsevin binding site on VDAC2. Finally, physiological consequences of the efsevininduced modulation of VDAC2 were analysed in HL-1 cardiomyocytes.Key Results: In lipid bilayers, efsevin reduced VDAC2 conductance and shifted the channel's open probability towards less anion-selective closed states. Efsevin binds to a binding pocket formed by the inner channel wall and the pore-lining N-terminal α-helix. Exchange of amino acids N207, K236 and N238 within this pocket for alanines abolished the channel's efsevin-responsiveness. Upon heterologous expression in HL-1 cardiomyocytes, both channels, wild-type VDAC2 and the efsevin-insensitive VDAC2 AAA restored mitochondrial Ca 2+ uptake, but only wild-type VDAC2 was sensitive to efsevin. Conclusion and Implications:In summary, our data indicate a direct interaction of efsevin with VDAC2 inside the channel pore that leads to modified gating and results in enhanced SR-mitochondria Ca 2+ transfer. This study sheds new light on the function of VDAC2 and provides a basis for structure-aided chemical optimization of efsevin.Abbreviations: CPVT, catecholaminergic polymorphic ventricular tachycardia; DPhPC, 1,2-diphytanoyl-sn-glycero-3-phosphatidylcholine; hVDAC2, human voltage-dependent anion channel 2; IRES, internal ribosome entry site; MCU, mitochondrial calcium uniporter; MOI, multiplicity of infection; mVDAC2, mouse voltage-dependent anion channel 2; OMM, outer mitochondrial membrane; P O , open probability; RuR, ruthenium red; shRNA, short hairpin RNA; SR, sarcoplasmic reticulum; VDAC, voltage-dependent anion channel; zVDAC2, zebrafish voltage-dependent anion channel 2.

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Section: Discussioncontrasting

confidence: 92%

Section: Discussionmentioning

confidence: 52%

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The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca²⁺ uptake

Wilting¹,

Kopp²,

Gurnev

et al. 2020

British J Pharmacology

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“…Authors concluded that this mechanism could explain the efsevin-induced facilitated transfer of calcium from the sarcoplasmic reticulum into mitochondria in zebra fish. Interestingly, in these studies, efsevin has not been observed to be involved in apoptosis (Schweitzer et al, 2017;Wilting et al, 2020) despite the accepted role of VDAC2 in apoptosis through recruitment of Bax or Bak (Cheng et al, 2003;Chin et al, 2018).…”

Section: Screening Non-polar Compounds For Vdac Functional Controlmentioning

confidence: 88%

“…Efsevin was demonstrated to bind to zebra fish VDAC2 (zfVDAC2) by an affinity pulldown assay (Shimizu et al, 2015). Efsevin is thought to enhance mitochondrial uptake of calcium through VDAC2, thereby preventing calcium accumulation in the cytosol (Schweitzer et al, 2017). Lately, using an in vitro system of reconstituted zfVDAC2 channels, Wilting et al (2020) found that efsevin promotes channel closure and shifts its selectivity toward less anionic thus, according to the previous studies (Rostovtseva et al, 2005;Tan and Colombini, 2007), ultimately causing an increase of VDAC2 permeability for calcium.…”

Section: Screening Non-polar Compounds For Vdac Functional Controlmentioning

confidence: 91%

Targeting the Multiple Physiologic Roles of VDAC With Steroids and Hydrophobic Drugs

et al. 2020

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There is accumulating evidence that endogenous steroids and non-polar drugs are involved in the regulation of mitochondrial physiology. Many of these hydrophobic compounds interact with the Voltage Dependent Anion Channel (VDAC). This major metabolite channel in the mitochondrial outer membrane (MOM) regulates the exchange of ions and water-soluble metabolites, such as ATP and ADP, across the MOM, thus governing mitochondrial respiration. Proteomics and biochemical approaches together with molecular dynamics simulations have identified an impressively large number of non-polar compounds, including endogenous, able to bind to VDAC. These findings have sparked speculation that both natural steroids and synthetic hydrophobic drugs regulate mitochondrial physiology by directly affecting VDAC ion channel properties and modulating its metabolite permeability. Here we evaluate recent studies investigating the effect of identified VDAC-binding natural steroids and non-polar drugs on VDAC channel functioning. We argue that while many compounds are found to bind to the VDAC protein, they do not necessarily affect its channel functions in vitro. However, they may modify other aspects of VDAC physiology such as interaction with its cytosolic partner proteins or complex formation with other mitochondrial membrane proteins, thus altering mitochondrial function.

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The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

Hamilton

Veress

Belevych

et al. 2021

Pflugers Arch - Eur J Physiol

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Sudden cardiac death due to malignant ventricular arrhythmias remains the major cause of mortality in the postindustrial world. Defective intracellular Ca2+ homeostasis has been well established as a key contributing factor to the enhanced propensity for arrhythmia in acquired cardiac disease, such as heart failure or diabetic cardiomyopathy. More recent advances provide a strong basis to the emerging view that hereditary cardiac arrhythmia syndromes are accompanied by maladaptive remodeling of Ca2+ homeostasis which substantially increases arrhythmic risk. This brief review will focus on functional changes in elements of Ca2+ handling machinery in cardiomyocytes that occur secondary to genetic mutations associated with catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome.

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Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models

Abstract: Visual Abstract

Cited by 40 publications

References 45 publications

The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca²⁺ uptake

The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca²⁺ uptake

Targeting the Multiple Physiologic Roles of VDAC With Steroids and Hydrophobic Drugs

The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

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Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models

Abstract: Visual Abstract

Cited by 40 publications

References 45 publications

The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca2+ uptake

The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca2+ uptake

Targeting the Multiple Physiologic Roles of VDAC With Steroids and Hydrophobic Drugs

The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

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Product

Resources

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The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca²⁺ uptake

The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca²⁺ uptake