Cell‐permeable succinate rescues mitochondrial respiration in cellular models of amiodarone toxicity
Bețiu, Alina M. ; Chamkha, Imen LU ; Gustafsson, Ellen ; Meijer, Elna ; Avram, Vlad F. ; Frostner, Eleonor Åsander LU
; Ehinger, Johannes K.
LU
; Petrescu, Lucian
; Muntean, Danina M.
and Elmér, Eskil
LU
(2021)
In International Journal of Molecular Sciences
22(21).
- Abstract
Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in hu-mans. It has previously been demonstrated that amiodarone and its metabolite (desethylamioda-rone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the elec-tron 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.... (More)
Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in hu-mans. It has previously been demonstrated that amiodarone and its metabolite (desethylamioda-rone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the elec-tron 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 con-centration‐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 in-creasing mitochondrial function using intracellular delivery of succinate.
(Less)
- author
- Bețiu, Alina M.
; Chamkha, Imen
LU
; Gustafsson, Ellen
; Meijer, Elna
; Avram, Vlad F.
; Frostner, Eleonor Åsander
LU
; Ehinger, Johannes K.
LU
; Petrescu, Lucian
; Muntean, Danina M.
and Elmér, Eskil
LU
- organization
- publishing date
- 2021-11-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Amiodarone, ATP, Desethylamiodarone, HepG2 cells, Mito-chondria, NV118, PBMCs, Platelets, Respiration, Sotalol
- in
- International Journal of Molecular Sciences
- volume
- 22
- issue
- 21
- article number
- 11786
- publisher
- MDPI AG
- external identifiers
-
- pmid:34769217
- scopus:85117932102
- ISSN
- 1661-6596
- DOI
- 10.3390/ijms222111786
- project
- Mitochondrial dysfunction in drug and chemical toxicity: mechanism, target identification and therapeutic development
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © by the authors. Licensee MDPI, Basel, Switzerland.
- id
- 79de9ede-a2bd-4e32-809c-3b22cfb22436
- date added to LUP
- 2021-11-22 13:54:56
- date last changed
- 2024-09-08 05:13:51
@article{79de9ede-a2bd-4e32-809c-3b22cfb22436,
abstract = {{<p>Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in hu-mans. It has previously been demonstrated that amiodarone and its metabolite (desethylamioda-rone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the elec-tron 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 con-centration‐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 in-creasing mitochondrial function using intracellular delivery of succinate.</p>}},
author = {{Bețiu, Alina M. and Chamkha, Imen and Gustafsson, Ellen and Meijer, Elna and Avram, Vlad F. and Frostner, Eleonor Åsander and Ehinger, Johannes K. and Petrescu, Lucian and Muntean, Danina M. and Elmér, Eskil}},
issn = {{1661-6596}},
keywords = {{Amiodarone; ATP; Desethylamiodarone; HepG2 cells; Mito-chondria; NV118; PBMCs; Platelets; Respiration; Sotalol}},
language = {{eng}},
month = {{11}},
number = {{21}},
publisher = {{MDPI AG}},
series = {{International Journal of Molecular Sciences}},
title = {{Cell‐permeable succinate rescues mitochondrial respiration in cellular models of amiodarone toxicity}},
url = {{http://dx.doi.org/10.3390/ijms222111786}},
doi = {{10.3390/ijms222111786}},
volume = {{22}},
year = {{2021}},
}