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Ciclopirox protects mitochondria from hydrogen peroxide toxicity.

ABSTRACT: 1 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 H2O2-induced mitochondrial injury by maintaining mitochondrial transmembrane potential (Deltapsim). 2 CPX completely blocked H2O2-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. 3 H2O2 rapidly depolarized the Deltapsim, and CPX blocked this H2O2-stimulated Deltapsim decrease. Similar data were obtained in experiments using mitochondria isolated from rat liver. 4 Furthermore, CPX effectively inhibited H2O2-induced mitochondrial permeability transition pore (MPTP) opening. In de-energized mitochondria, however, CPX did not inhibit Ca2+-evoked MPTP opening, indicating that CPX is not a direct inhibitor of the MPTP. 5 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 H2O2. Consistent with this, CPX replenished ATP levels lowered by H2O2. 6 The present results indicate that CPX protects SK-HEP-1 cells from H2O2 cytotoxicity by inhibiting Deltapsim decrease and indirectly preventing MPTP opening.

SUBMITTER: Lee SJ

PROVIDER: S-EPMC1576158 | biostudies-other | 2005 Jun

REPOSITORIES: biostudies-other

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Project description:Cell apoptosis is a biochemical and molecular pathway essential for maintaining cellular homeostasis. It is an integrated process involving in a series of signal transduction cascades. Moreover, the apoptotic pathways may be initiated inside various subcellular organelles. Increasing evidence indicates that hydrogen peroxide (H2O2) is closely related to cell apoptosis, particularly in the mitochondria. However, during the apoptotic process, the synergetic variation of H2O2 levels in different compartments is seldom explored, particularly in two important organelles: mitochondria and endoplasmic reticulum (ER). To solve this problem, we developed two new organelle-specific fluorescent probes termed MI-H2O2 and ER-H2O2 that can detect H2O2 in mitochondria and ER, respectively or simultaneously. Experimental results demonstrated that MI-H2O2 and ER-H2O2 display distinguishable excitation and emission spectra, as well as excellent organelle targeting capabilities. Therefore, we used MI-H2O2 and ER-H2O2 to successfully image exogenous or endogenous hydrogen peroxide in the mitochondria and ER. Interestingly, during diverse apoptotic stimuli, dual-color fluorescence imaging results revealed that the changes of H2O2 levels in mitochondria and ER are different. The H2O2 levels are enhanced in both the mitochondria and ER during the l-buthionine sulfoximine (BSO)-treated cell apoptosis process. During mitochondria-oriented apoptosis induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP) or rotenone, H2O2 levels prominently and continuously increase in the mitochondria, whereas the ER H2O2 levels were found to rise subsequently after a delay. Moreover, during ER-oriented apoptosis induced by tunicamycin, ER is the major site for overproduction of H2O2, and delayed elevation of the H2O2 levels was found in the mitochondria. Altogether, this dual-probe and multicolor imaging approach may offer a proven methodology for studying molecular communication events on H2O2-related apoptosis and also other physiological and pathological processes within different subcellular organelles.

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Ciclopirox protects mitochondria from hydrogen peroxide toxicity.

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