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

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 syst...

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Autores principales:	Alina M. Bețiu, Imen Chamkha, Ellen Gustafsson, Elna Meijer, Vlad F. Avram, Eleonor Åsander Frostner, Johannes K. Ehinger, Lucian Petrescu, Danina M. Muntean, Eskil Elmér
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	amiodarone desethylamiodarone sotalol NV118 platelets PBMCs Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/7fda1e668c234b2e996f3e85b34b882d
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spelling	oai:doaj.org-article:7fda1e668c234b2e996f3e85b34b882d2021-11-11T17:14:12ZCell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity10.3390/ijms2221117861422-00671661-6596https://doaj.org/article/7fda1e668c234b2e996f3e85b34b882d2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11786https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Amiodarone 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.Alina M. BețiuImen ChamkhaEllen GustafssonElna MeijerVlad F. AvramEleonor Åsander FrostnerJohannes K. EhingerLucian PetrescuDanina M. MunteanEskil ElmérMDPI AGarticleamiodaronedesethylamiodaronesotalolNV118plateletsPBMCsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11786, p 11786 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	amiodarone desethylamiodarone sotalol NV118 platelets PBMCs Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	amiodarone desethylamiodarone sotalol NV118 platelets PBMCs Biology (General) QH301-705.5 Chemistry QD1-999 Alina M. Bețiu Imen Chamkha Ellen Gustafsson Elna Meijer Vlad F. Avram Eleonor Åsander Frostner Johannes K. Ehinger Lucian Petrescu Danina M. Muntean Eskil Elmér Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity
description	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.
format	article
author	Alina M. Bețiu Imen Chamkha Ellen Gustafsson Elna Meijer Vlad F. Avram Eleonor Åsander Frostner Johannes K. Ehinger Lucian Petrescu Danina M. Muntean Eskil Elmér
author_facet	Alina M. Bețiu Imen Chamkha Ellen Gustafsson Elna Meijer Vlad F. Avram Eleonor Åsander Frostner Johannes K. Ehinger Lucian Petrescu Danina M. Muntean Eskil Elmér
author_sort	Alina M. Bețiu
title	Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity
title_short	Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity
title_full	Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity
title_fullStr	Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity
title_full_unstemmed	Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity
title_sort	cell-permeable succinate rescues mitochondrial respiration in cellular models of amiodarone toxicity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7fda1e668c234b2e996f3e85b34b882d
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Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity

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