Ciclopirox protects mitochondria from hydrogen peroxide toxicity.
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.
Lee
Sun J
SJ
Department of Pharmacology, College of Medicine, Ewha Institute of Neuroscience, Tongdaemoon Hospital, Ewha Womans University, 70 Chongro-6-ga, Chongroku, Seoul 110-783, Republic of Korea.
Jin
Youngnam
Y
Yoon
Hye Young
HY
Choi
Byung-Ok
BO
Kim
Hyoung Chun
HC
Oh
Yu-Kyoung
YK
Kim
Hee-Sun
HS
Kim
Won-Ki
WK
D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077768:Ciclopirox; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011728:Pyridones / Q000494:pharmacology*; D011773:Pyruvates / Q000378:metabolism; D013997:Time Factors
D005971:Glutamates; D008293:Malates; D011728:Pyridones; D011773:Pyruvates; D000077768:Ciclopirox; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D000154:Aconitate Hydratase; D002118:Calcium