Ciclopirox protects mitochondria from hydrogen peroxide toxicity

Sun J. Lee; Youngman Jin; Hye Young Yoon; Byung Ok Choi; Hyoung Chun Kim; Yu Kyoung Oh; Hee Sun Kim; Woo Ki Kim

doi:10.1038/sj.bjp.0706206

Ciclopirox protects mitochondria from hydrogen peroxide toxicity

Sun J. Lee, Youngman Jin, Hye Young Yoon, Byung Ok Choi, Hyoung Chun Kim, Yu Kyoung Oh, Hee Sun Kim, Woo Ki Kim

Department of Molecular Medicine

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

The mitochondrial respiratory chain produces reactive oxygen species (ROS) during normal electron transport. Despite producing ROS, mitochondria are vulnerable to oxidative stress. Mitochondrial dysfunction has been associated with many degenerative diseases, making it important to identify compounds that protect mitochondria from ROS-mediated toxicity. Here we report that ciclopirox (CPX) blocks H ₂O ₂-induced mitochondrial injury by maintaining mitochondrial transmembrane potential (Δψm). CPX completely blocked H ₂O ₂-stimulated release of lactate dehydrogenase (a marker of cell death) and decrease in MTT reduction (a marker of mitochondrial function) in adenocarcinoma SK-HEP-1 cells. H ₂O ₂ rapidly depolarized the Δψm, and CPX blocked this H ₂O ₂-stimulated Δψm decrease. Similar data were obtained in experiments using mitochondria isolated from rat liver. Furthermore, CPX effectively inhibited H ₂O ₂-induced mitochondrial permeability transition pore (MPTP) opening. In de-energized mitochondria, however, CPX did not inhibit Ca ²⁺-evoked MPTP opening, indicating that CPX is not a direct inhibitor of the MPTP. Oxygen consumption studies showed that in the presence of pyruvate and malate CPX restored the rate of state 3 to state 4 respiration decreased by H ₂O ₂. Consistent with this, CPX replenished ATP levels lowered by H ₂O ₂. The present results indicate that CPX protects SK-HEP-1 cells from H ₂O ₂ cytotoxicity by inhibiting Δψm decrease and indirectly preventing MPTP opening.

Original language	English
Pages (from-to)	469-476
Number of pages	8
Journal	British Journal of Pharmacology
Volume	145
Issue number	4
DOIs	https://doi.org/10.1038/sj.bjp.0706206
State	Published - Jun 2005

Keywords

Cell death
Ciclopirox
Hydrogen peroxide
Mitochondrial permeability transition pore
Mitochondrial transmembrane potential

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10.1038/sj.bjp.0706206

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@article{f181ab9d1afc49e48cf618c21641f53b,

title = "Ciclopirox protects mitochondria from hydrogen peroxide toxicity",

abstract = "The mitochondrial respiratory chain produces reactive oxygen species (ROS) during normal electron transport. Despite producing ROS, mitochondria are vulnerable to oxidative stress. Mitochondrial dysfunction has been associated with many degenerative diseases, making it important to identify compounds that protect mitochondria from ROS-mediated toxicity. Here we report that ciclopirox (CPX) blocks H 2O 2-induced mitochondrial injury by maintaining mitochondrial transmembrane potential (Δψm). CPX completely blocked H 2O 2-stimulated release of lactate dehydrogenase (a marker of cell death) and decrease in MTT reduction (a marker of mitochondrial function) in adenocarcinoma SK-HEP-1 cells. H 2O 2 rapidly depolarized the Δψm, and CPX blocked this H 2O 2-stimulated Δψm decrease. Similar data were obtained in experiments using mitochondria isolated from rat liver. Furthermore, CPX effectively inhibited H 2O 2-induced mitochondrial permeability transition pore (MPTP) opening. In de-energized mitochondria, however, CPX did not inhibit Ca 2+-evoked MPTP opening, indicating that CPX is not a direct inhibitor of the MPTP. Oxygen consumption studies showed that in the presence of pyruvate and malate CPX restored the rate of state 3 to state 4 respiration decreased by H 2O 2. Consistent with this, CPX replenished ATP levels lowered by H 2O 2. The present results indicate that CPX protects SK-HEP-1 cells from H 2O 2 cytotoxicity by inhibiting Δψm decrease and indirectly preventing MPTP opening.",

keywords = "Cell death, Ciclopirox, Hydrogen peroxide, Mitochondrial permeability transition pore, Mitochondrial transmembrane potential",

author = "Lee, {Sun J.} and Youngman Jin and Yoon, {Hye Young} and Choi, {Byung Ok} and Kim, {Hyoung Chun} and Oh, {Yu Kyoung} and Kim, {Hee Sun} and Kim, {Woo Ki}",

year = "2005",

month = jun,

doi = "10.1038/sj.bjp.0706206",

language = "English",

volume = "145",

pages = "469--476",

journal = "British Journal of Pharmacology",

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publisher = "John Wiley and Sons Inc.",

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TY - JOUR

T1 - Ciclopirox protects mitochondria from hydrogen peroxide toxicity

AU - Lee, Sun J.

AU - Jin, Youngman

AU - Yoon, Hye Young

AU - Choi, Byung Ok

AU - Kim, Hyoung Chun

AU - Oh, Yu Kyoung

AU - Kim, Hee Sun

AU - Kim, Woo Ki

PY - 2005/6

Y1 - 2005/6

N2 - The mitochondrial respiratory chain produces reactive oxygen species (ROS) during normal electron transport. Despite producing ROS, mitochondria are vulnerable to oxidative stress. Mitochondrial dysfunction has been associated with many degenerative diseases, making it important to identify compounds that protect mitochondria from ROS-mediated toxicity. Here we report that ciclopirox (CPX) blocks H 2O 2-induced mitochondrial injury by maintaining mitochondrial transmembrane potential (Δψm). CPX completely blocked H 2O 2-stimulated release of lactate dehydrogenase (a marker of cell death) and decrease in MTT reduction (a marker of mitochondrial function) in adenocarcinoma SK-HEP-1 cells. H 2O 2 rapidly depolarized the Δψm, and CPX blocked this H 2O 2-stimulated Δψm decrease. Similar data were obtained in experiments using mitochondria isolated from rat liver. Furthermore, CPX effectively inhibited H 2O 2-induced mitochondrial permeability transition pore (MPTP) opening. In de-energized mitochondria, however, CPX did not inhibit Ca 2+-evoked MPTP opening, indicating that CPX is not a direct inhibitor of the MPTP. Oxygen consumption studies showed that in the presence of pyruvate and malate CPX restored the rate of state 3 to state 4 respiration decreased by H 2O 2. Consistent with this, CPX replenished ATP levels lowered by H 2O 2. The present results indicate that CPX protects SK-HEP-1 cells from H 2O 2 cytotoxicity by inhibiting Δψm decrease and indirectly preventing MPTP opening.

AB - The mitochondrial respiratory chain produces reactive oxygen species (ROS) during normal electron transport. Despite producing ROS, mitochondria are vulnerable to oxidative stress. Mitochondrial dysfunction has been associated with many degenerative diseases, making it important to identify compounds that protect mitochondria from ROS-mediated toxicity. Here we report that ciclopirox (CPX) blocks H 2O 2-induced mitochondrial injury by maintaining mitochondrial transmembrane potential (Δψm). CPX completely blocked H 2O 2-stimulated release of lactate dehydrogenase (a marker of cell death) and decrease in MTT reduction (a marker of mitochondrial function) in adenocarcinoma SK-HEP-1 cells. H 2O 2 rapidly depolarized the Δψm, and CPX blocked this H 2O 2-stimulated Δψm decrease. Similar data were obtained in experiments using mitochondria isolated from rat liver. Furthermore, CPX effectively inhibited H 2O 2-induced mitochondrial permeability transition pore (MPTP) opening. In de-energized mitochondria, however, CPX did not inhibit Ca 2+-evoked MPTP opening, indicating that CPX is not a direct inhibitor of the MPTP. Oxygen consumption studies showed that in the presence of pyruvate and malate CPX restored the rate of state 3 to state 4 respiration decreased by H 2O 2. Consistent with this, CPX replenished ATP levels lowered by H 2O 2. The present results indicate that CPX protects SK-HEP-1 cells from H 2O 2 cytotoxicity by inhibiting Δψm decrease and indirectly preventing MPTP opening.

KW - Cell death

KW - Ciclopirox

KW - Hydrogen peroxide

KW - Mitochondrial permeability transition pore

KW - Mitochondrial transmembrane potential

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DO - 10.1038/sj.bjp.0706206

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SP - 469

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JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

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ER -

Ciclopirox protects mitochondria from hydrogen peroxide toxicity

Abstract

Keywords

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