Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity.

Alina M Bețiu,Imen Chamkha,Johannes K Ehinger,Eskil Elmér,Ellen Gustafsson,Lucian Petrescu,Vlad F Avram,Danina M Muntean,Elna Meijer,Eleonor Åsander Frostner

doi:10.3390/ijms222111786

Abstract

Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in humans. It has previously been demonstrated that amiodarone and its metabolite (desethylamiodarone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the electron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver-derived human cell line, is primarily aimed at assessing the concentration-dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell-permeable succinate prodrug in alleviating the drug-induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a concentration-dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI- and CII-supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration-dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by increasing mitochondrial function using intracellular delivery of succinate.

Highlights

Mitochondrial respiration of intact human platelets was assessed in the presence of increasing concentrations of amiodarone and sotalol (15–240 μM), respectively
Significant concentration-dependent respiratory inhibition was elicited by amiodarone with a reduction of mitochondrial oxygen consumption to 23.4% ± 9.5 (p < 0.01) of control (Figure 1A,B)
We have shown here that amiodarone causes a concentration-dependent reduction have shown here that amiodarone causes a concentration-dependent reduction in mito-in mitochondrial consumption of human platelets, leading to an overall decrease chondrial oxygenoxygen consumption of human platelets, leading to an overall decrease in P-Lin

Summary

Introduction

Cardiac arrhythmias are conditions defined by an irregular heartbeat that can arise from either atria or ventricles [1]. Amiodarone is the most effective class III (VaughanWilliams’ classification) antiarrhythmic drug, widely used to treat both ventricular and supraventricular arrhythmias [2]. The new European Society of Cardiology Guidelines for the diagnosis and management of atrial fibrillation recommend amiodarone for long-term rhythm control in all patients with atrial fibrillation, including those with heart failure [3]. Desethylamiodarone, the main metabolite of amiodarone, possesses antiarrhythmic properties via the N-demethylation reaction catalyzed by cytochrome P450 3A4 [4,5]

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