Abstract
It is generally considered that reactive oxygen species (ROS) are involved in the development of numerous pathologies. The level of ROS can be altered via the uncoupling of oxidative phosphorylation by using protonophores causing mitochondrial membrane depolarization. Here, we report that the uncoupling activity of potent protonophores, such as carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), carbonyl cyanide 3-chlorophenylhydrazone (CCCP), and fluazinam, can be abrogated by the addition of thiol-containing antioxidants to isolated mitochondria. In particular, N-acetylcysteine, glutathione, cysteine, and dithiothreitol removed both a decrease in the mitochondrial membrane potential and an increase in the respiration rate that is caused by FCCP. The thiols also reduced the electrical current that is induced by FCCP and CCCP across planar bilayer lipid membranes. Thus, when speculating on the mechanistic roles of ROS level modulation by mitochondrial uncoupling based on the antioxidant reversing certain FCCP and CCCP effects on cellular processes, one should take into account the ability of these protonophoric uncouplers to directly interact with the thiol-containing antioxidants.
Highlights
At present, there is a common opinion that the oxidative stress is causative of a plethora of serious diseases, including neurodegenerative disorders, heart failure, kidney pathologies, and endocrine system malfunction
The involvement of reactive oxygen species (ROS) level modulation by carbonyl cyanide 3-chlorophenylhydrazone (CCCP), FCCP, and fluazinam in certain cellular processes was validated by the sensitivity of the uncoupler impacts on these processes to NAC [13,14,15,16,17]
We demonstrated the suppression of the protonophoric activity of CCCP and FCCP
Summary
There is a common opinion that the oxidative stress is causative of a plethora of serious diseases, including neurodegenerative disorders, heart failure, kidney pathologies, and endocrine system malfunction. According to a series of papers [1,2,3,4,5,6,7,8], the uncoupling of oxidative phosphorylation in mitochondria can significantly affect the generation of reactive oxygen species (ROS) In view of these results, the modulation of the ROS level by uncouplers was considered as the basis of their protective action against numerous diseases [9,10,11]. We performed a thorough investigation of functional consequences of the interaction of CCCP, FCCP, and fluazinam with thiol antioxidants, in particular, their impact on the ability of these uncouplers to decrease mitochondrial membrane potential and accelerate respiration of isolated mitochondria. We demonstrated the suppression of the protonophoric activity of CCCP and FCCP in model lipid bilayer membranes
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