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

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.

The Pharmacological Effects of Silver Nanoparticles Functionalized with Eptifibatide on Platelets and Endothelial Cells

“… 21 For mitochondria respiration experiments, platelets were prepared as previously described. 22 For coagulation studies, 3 mL of blood was collected using 3.8% buffered sodium citrate and prepared according to the reference recommendations for each method.…”

Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed

“…Amiodarone was also reported to decrease the intracellular ATP content both in vivo in a rat model of hepatotoxicity [ 129 ] and in vitro in isolated rat liver mitochondria, human hepatocytes [ 130 ] and in rat H9c2 cardiomyocytes [ 131 ]. A recent study has shown that acute administration of amiodarone induced a concentration-dependent mitochondrial dysfunction in human platelets, peripheral blood mononuclear cells and HepG2 cells by inhibiting both CI- and CII-supported respiration [ 33 ]. Additionally, in peripheral blood mononuclear cells, amiodarone determined a severe concentration-dependent ATP depletion [ 33 ].…”

“…A recent study has shown that acute administration of amiodarone induced a concentration-dependent mitochondrial dysfunction in human platelets, peripheral blood mononuclear cells and HepG2 cells by inhibiting both CI- and CII-supported respiration [ 33 ]. Additionally, in peripheral blood mononuclear cells, amiodarone determined a severe concentration-dependent ATP depletion [ 33 ]. Since the latter study was purported to investigate the drug toxicity, it must be mentioned that amiodarone was applied in concentrations varying between 20 and 400 μM (while plasma level of amiodarone is in the range of ~2μM) [ 33 ].…”

“…Additionally, in peripheral blood mononuclear cells, amiodarone determined a severe concentration-dependent ATP depletion [ 33 ]. Since the latter study was purported to investigate the drug toxicity, it must be mentioned that amiodarone was applied in concentrations varying between 20 and 400 μM (while plasma level of amiodarone is in the range of ~2μM) [ 33 ].…”

“…Sotalol, a non-selective β-adrenergic blocking agent classified as a class III antiarrhythmic agent due to its predominant potassium channel blocking effect is used for the treatment of supraventricular arrhythmias, atrial fibrillation/flutter as well as for the management of ventricular arrhythmias [ 243 ]. Recently, in human platelets, it has been demonstrated that sotalol did not elicit mitochondrial dysfunction in acute administration [ 33 ].…”