Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I
Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative cont...
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doaj-724c956be5c74257a702e577874aa26c2020-11-25T01:32:02ZengElsevierRedox Biology2213-23172015-04-014C27928810.1016/j.redox.2015.01.005Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex INaoki Imaizumi0Kang Kwang Lee1Carmen Zhang2Urs A. Boelsterli3Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USADepartment of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USADepartment of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USADepartment of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD+ ratio. We used the antiviral drug efavirenz (EFV) to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30 µM EFV and submaximal effects at 50 µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD). This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD+ ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40 µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical. http://www.sciencedirect.com/science/article/pii/S2213231715000063Sirt3EfavirenzComplex I inhibitionMitochondriaPeroxynitriteDrug-induced liver injury (DILI) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Naoki Imaizumi Kang Kwang Lee Carmen Zhang Urs A. Boelsterli |
spellingShingle |
Naoki Imaizumi Kang Kwang Lee Carmen Zhang Urs A. Boelsterli Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I Redox Biology Sirt3 Efavirenz Complex I inhibition Mitochondria Peroxynitrite Drug-induced liver injury (DILI) |
author_facet |
Naoki Imaizumi Kang Kwang Lee Carmen Zhang Urs A. Boelsterli |
author_sort |
Naoki Imaizumi |
title |
Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I |
title_short |
Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I |
title_full |
Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I |
title_fullStr |
Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I |
title_full_unstemmed |
Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I |
title_sort |
mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex i |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2015-04-01 |
description |
Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD+ ratio. We used the antiviral drug efavirenz (EFV) to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30 µM EFV and submaximal effects at 50 µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD). This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD+ ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40 µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical.
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topic |
Sirt3 Efavirenz Complex I inhibition Mitochondria Peroxynitrite Drug-induced liver injury (DILI) |
url |
http://www.sciencedirect.com/science/article/pii/S2213231715000063 |
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