Redox-cycling compounds can cause the permeabilization of mitochondrial membranes by mechanisms other than ROS production.
The participation of reactive oxygen species (ROS) in the regulation of mitochondrial permeability transition pore (mPTP) opening by the redox-cycling compounds menadione and lucigenin was explored. The level of ROS was modulated by antioxidants, anoxia, and switching the sites of the reduction of redox cyclers, the dehydrogenases of the inner and outer mitochondrial membranes. We found that the reduction of both lucigenin and menadione in the outer mitochondrial membrane caused a strong production of ROS. However, mPTP opening was accelerated only in the presence of the cationic acceptor lucigenin. The antioxidants and scavengers of ROS that considerably decreased the level of ROS in mitochondria did not prevent or delay the mPTP opening. If the transmembrane potential under anoxia was supported by exogenous ATP or ferricyanide, the permeabilization of mitochondrial membranes by menadione or lucigenin was the same as under normoxia or even more pronounced. Under anoxia, the lucigenin-dependent permeabilization of membranes was less sensitive to mPTP antagonists than under normoxia. We conclude that the opening of the mPTP by redox cyclers may be independent of ROS and is due to the direct oxidation of mitochondrial pyridine nucleotides by menadione and the modification of critical thiols of the mPTP by the cation radical of lucigenin.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya, 3, 142290 Pushchino, Moscow Region, Russia. krugalex@rambler.ru
Alexey G
AG
Kruglov
Ksenia B
KB
Subbotina
Nils-Erik L
NE
Saris
D000166:Acridines / Q000494:pharmacology; D000818:Animals; D002463:Cell Membrane Permeability; D005978:Glutathione / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008933:Mitochondrial Swelling; D009243:NAD / Q000502:physiology; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D024483:Vitamin K 3 / Q000494:pharmacology
D000166:Acridines; D017382:Reactive Oxygen Species; D009243:NAD; C033472:10,10'-dimethyl-9,9'-biacridinium; D024483:Vitamin K 3; D005978:Glutathione