Modulation of the permeability transition pore by inhibition of the mitochondrial K(ATP) channel in liver vs. brain mitochondria.
Inhibition of the mitochondrial K(ATP) (mitoK(ATP)) channel abrogates the beneficial effects of preconditioning induced by a brief episode of sublethal ischemia. We studied the effect of 5-hydroxydecanoate, a well-known inhibitor of the mitoK(ATP) channel, on swelling of isolated liver and brain mitochondria. Volume changes were determined by measurement of light absorbance at 540 nm. Mitochondrial swelling induced by adding Ca(2+ )ions correlated with opening of the permeability transition pore as shown by modulation by 1 microM cyclosporin A. In brain mitochondria, 5-hydroxydecanoate did not significantly affect Ca(2+)-induced swelling. In contrast, 50 or 500 microM 5-hydroxydecanoate increased swelling of liver mitochondria by 9.7 +/- 5.1% (n = 6, P = 0.057) and 29.4 +/- 1.4% (n = 5, P < 0.0001), respectively. The effect of 5-hydroxydecanoate was blocked by cyclosporin A and was dependent on the presence of potassium in the medium. In medium containing 200 microM ATP to inhibit the mitoK(ATP )channel, 5-hydroxydecanoate did not further increase Ca(2+)-induced swelling. We conclude that inhibition of the mitoK(ATP) channel exerts its detrimental effect by facilitation of permeability transition pore opening.
Kupsch
K
K
Institute of Medical Neurobiology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany. kathleen.kupsch@medizin.uni-magdeburg.de
Parvez
S
S
Siemen
D
D
Wolf
G
G
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D003652:Decanoic Acids; D006880:Hydroxy Acids; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D002118:Calcium