PROTONOPHORIC ACTIVITY OF FATTY-ACID ANALOGS AND DERIVATIVES IN THE INNER MITOCHONDRIAL-MEMBRANE - A FURTHER ARGUMENT FOR THE FATTY-ACID CYCLING MODEL

The protonophoric (uncoupling) action of various long-chain fatty acid s and their derivatives in mitochondria was investigated as related to their ability for rapid transbilayer movement in the inner mitochondr ial membrane (flip-flop) and interaction with the ADP/ATP carrier (AAC ), Flip-flop was assessed from a rapid decrease of internal mitochondr ial pH. It was found that long-chain unsubstituted fatty acids (with t he exception of very-long-chain unbranched homologs) and their thia an d oxa analogs performed a rapid flip-flop, inhibited AAC activity and increased proton permeability of the inner mitochondrial membrane, res ulting in dissipation of mitochondrial membrane potential and increase d resting state respiration. Bipolar fatty acid analogs, i.e., those c ontaining a second carboxylic group or OH group(s) at the hydrocarbon tail, phenyl-substituted fatty acid derivatives, and fatty acid analog s containing strongly ionized sulfonyl or sulfate groups instead of th e carboxylic group, did not flip-flop and were not uncoupling, althoug h some of them were weak inhibitors of AAC, These results provide furt her confirmation of the fatty acid cycling model (V. P. Skulachev, FEB S Lett. 294, 158-162, 1991) in which the protonophoric function of fat ty acids is a result of the spontaneous transbilayer passage of undiss ociated (protonated) molecules of the fatty acid from the external sid e of the inner mitochondrial membrane to the matrix side and the AAC-m ediated transport of the fatty acid anion in the opposite direction. ( C) 1998 Academic Press.