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Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose

Piel, Sarah LU ; Chamkha, Imen LU ; Kozak Dehlin, Adam ; Ehinger, Johannes K. LU ; Sjövall, Fredrik LU ; Elmér, Eskil LU and Hansson, Magnus J. LU (2020) In PLoS ONE 15(4).
Abstract

Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it... (More)

Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.

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publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
15
issue
4
article number
e0231173
publisher
Public Library of Science
external identifiers
  • pmid:32251487
  • scopus:85082926988
ISSN
1932-6203
DOI
10.1371/journal.pone.0231173
language
English
LU publication?
yes
id
a73c6055-448c-4ee9-b365-d7de51ed6d5e
date added to LUP
2020-05-11 14:07:17
date last changed
2021-04-11 04:42:49
@article{a73c6055-448c-4ee9-b365-d7de51ed6d5e,
  abstract     = {<p>Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.</p>},
  author       = {Piel, Sarah and Chamkha, Imen and Kozak Dehlin, Adam and Ehinger, Johannes K. and Sjövall, Fredrik and Elmér, Eskil and Hansson, Magnus J.},
  issn         = {1932-6203},
  language     = {eng},
  number       = {4},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose},
  url          = {http://dx.doi.org/10.1371/journal.pone.0231173},
  doi          = {10.1371/journal.pone.0231173},
  volume       = {15},
  year         = {2020},
}