Effect of ebselen on Ca2+ transport in mitochondria.
The seleno-organic compound ebselen mimics the glutathione-dependent, hydroperoxide reducing activity of glutathione peroxidase. The activity of glutathione peroxidase determines the rate of hydroperoxide-induced Ca2+ release from mitochondria. Ebselen stimulates Ca2+ release from mitochondria, accelerates mitochondrial respiration and uncoupling, and induces mitochondrial swelling, indicating a deterioration of mitochondrial function. These manifestations are abolished by cyclosporine A, a potent inhibitor of the mitochondrial permeability transition. However, when ebselen-induced Ca2+ cycling is prevented with ruthenium red, an inhibitor of the Ca2+ uniporter, or by chelation of extramitochondrial Ca2+ by EGTA, no detectable elevation of swelling or uncoupling is observed. The release of Ca2+ from mitochondria is delayed in the absence of rotenone, i.e. when pyridine nucleotides are maintained in the reduced state due to succinate-driven reversed electron flow. We suggest that ebselen induces Ca2+ release from intact mitochondria via an NAD+ hydrolysis-dependent mechanism.
Gogvadze
V
V
Department of Molecular and Cell Biology, University of California, Berkeley, USA.
Klein
S D
SD
Shigenaga
M
M
Ames
B N
BN
Richter
C
C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D054833:Isoindoles; D007659:Ketones / Q000494:pharmacology; D007700:Kinetics; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D000975:Antioxidants; D001393:Azoles; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D054833:Isoindoles; D007659:Ketones; D016566:Organoselenium Compounds; D014475:Uncoupling Agents; C034703:mitochondrial calcium uniporter; D012430:Ruthenium Red; C042986:ebselen; D004533:Egtazic Acid; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016572:Cyclosporine; C018637:phorone; D005978:Glutathione; D002118:Calcium