Fatty acid-induced uncoupling of oxidative phosphorylation is partly due to opening of the mitochondrial permeability transition pore.
Addition of myristate at low concentration (30-60 nmol/mg protein) to energized rat liver mitochondria resulted in dissipation of the electric membrane potential which, in Ca2+-free media, could be partly reversed by carboxyatractyloside but not by cyclosporin A. In contrast, in mitochondria preloaded with Ca2+ this energy-dissipating effect of fatty acid was partly prevented or reversed by cyclosporin A or ADP. In sucrose media, myristate, but not the protonophore carbonyl cyanide m-chlorophenylhydrazone, induced swelling of Ca2+-loaded mitochondria which was inhibited by cyclosporin A and ADP. We conclude that long-chain fatty acids may induce opening of the mitochondrial permeability transition pore not only because of their protonophoric effect mediated by mitochondrial anion carriers [Skulachev, V.P., FEBS Lett. 294 (1991) 158-162; Wieckowski, M.R. and Wojtczak, L., Biochem. Biophys. Res. Commun. (1997) 232, 414-417] but also by a direct interaction with the pore assembly.
Wieckowski
M R
MR
Nencki Institute of Experimental Biology, Warsaw, Poland.
Wojtczak
L
L
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects*; D007473:Ion Channels / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000502:physiology*; D008930:Mitochondria, Liver / Q000187:drug effects*; D008933:Mitochondrial Swelling / Q000187:drug effects; D019814:Myristic Acid / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D018272:Porins; D051381:Rats; D011919:Rats, Inbred Strains; D014475:Uncoupling Agents / Q000494:pharmacology; D050994:Voltage-Dependent Anion Channels
D005227:Fatty Acids; D007473:Ion Channels; D008565:Membrane Proteins; D018272:Porins; D014475:Uncoupling Agents; D050994:Voltage-Dependent Anion Channels; D019814:Myristic Acid; D001278:Atractyloside; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000244:Adenosine Diphosphate; D016572:Cyclosporine; C003853:carboxyatractyloside; D002118:Calcium