Document Detail

Cyclosporin A-sensitive decrease in the transmembrane potential across the inner membrane of liver mitochondria induced by low concentrations of fatty acids and Ca2+.
MedLine Citation:
PMID:  12765520     Owner:  NLM     Status:  MEDLINE    
At low Ca2+ concentrations the pore of the inner mitochondrial membrane can open in substates with lower permeability (Hunter, D. R., and Haworth, R. A. (1979) Arch. Biochem. Biophys., 195, 468-477). Recently, we showed that Ca2+ loading of mitochondria augments the cyclosporin A-dependent decrease in transmembrane potential (DeltaPsi) across the inner mitochondrial membrane caused by 10 micro M myristic acid but does not affect the stimulation of respiration by this fatty acid. We have proposed that in our experiments the pore opened in a substate with lower permeability rather than in the "classic" state (Bodrova, M. E., et al. (2000) IUBMB Life, 50, 189-194). Here we show that under conditions lowering the probability of "classic pore" opening in Ca2+-loaded mitochondria myristic acid induces the cyclosporin A-sensitive DeltaPsi decrease and mitochondrial swelling more effectively than uncoupler SF6847 does, though their protonophoric activities are equal. In the absence of P(i) and presence of succinate and rotenone (with or without glutamate) cyclosporin A either reversed or only stopped DeltaPsi decrease induced by 5 micro M myristic acid and 5 micro M Ca2+. In the last case nigericin, when added after cyclosporin A, reversed the DeltaPsi decrease, and the following addition of EGTA produced only a weak (if any) DeltaPsi increase. In P(i)-containing medium (in the presence of glutamate and malate) cyclosporin A reversed the DeltaPsi decrease. These data show that the cyclosporin A-sensitive decrease in DeltaPsi by low concentrations of fatty acids and Ca2+ cannot be explained by specific uncoupling effect of fatty acid. We propose that: 1) low concentrations of Ca2+ and fatty acid induce the pore opening in a substate with a selective cation permeability, and the cyclosporin A-sensitive DeltaPsi decrease results from a conversion of DeltaPsi to pH gradient due to the electrogenic cation transport in mitochondria; 2) the ADP/ATP-antiporter is involved in this process; 3) higher efficiency of fatty acid compared to SF6847 in the Ca2+-dependent pore opening seems to be due to its interaction with the nucleotide-binding site of the ADP/ATP-antiporter and higher affinity of fatty acids to cations.
M E Bodrova; I V Brailovskaya; G I Efron; A A Starkov; E N Mokhova
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry. Biokhimii͡a     Volume:  68     ISSN:  0006-2979     ISO Abbreviation:  Biochemistry Mosc.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-05-26     Completed Date:  2004-04-13     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376536     Medline TA:  Biochemistry (Mosc)     Country:  United States    
Other Details:
Languages:  eng     Pagination:  391-8     Citation Subset:  IM    
Belozersky Institute for Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia.
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MeSH Terms
Calcium / pharmacology*
Cyclosporine / pharmacology*
Dose-Response Relationship, Drug
Fatty Acids / pharmacology*
Glutamic Acid / chemistry,  metabolism
Intracellular Membranes / drug effects,  physiology
Malates / chemistry,  metabolism
Membrane Potentials / drug effects
Mitochondria, Liver / drug effects,  physiology*
Mitochondrial ADP, ATP Translocases / metabolism
Myristic Acid / pharmacology
Nigericin / pharmacology
Nitriles / pharmacology
Substrate Specificity
Uncoupling Agents / pharmacology
Reg. No./Substance:
0/Fatty Acids; 0/Malates; 0/Nitriles; 0/Uncoupling Agents; 28380-24-7/Nigericin; 51601-81-1/SF 6847; 544-63-8/Myristic Acid; 56-86-0/Glutamic Acid; 59865-13-3/Cyclosporine; 6915-15-7/malic acid; 7440-70-2/Calcium; 9068-80-8/Mitochondrial ADP, ATP Translocases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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