LOW CONCENTRATIONS OF CYCLOSPORINE-A RESEAL THE PERMEABILITY TRANSITION PORE OF THE INNER MITOCHONDRIAL-MEMBRANE IN THE ABSENCE OF ADDITIONAL EFFECTORS

Citation
Ye. Kushnareva et al., LOW CONCENTRATIONS OF CYCLOSPORINE-A RESEAL THE PERMEABILITY TRANSITION PORE OF THE INNER MITOCHONDRIAL-MEMBRANE IN THE ABSENCE OF ADDITIONAL EFFECTORS, Biochemistry, 60(9), 1995, pp. 1145-1152
Citations number
29
Categorie Soggetti
Biology
Journal title
ISSN journal
00062979
Volume
60
Issue
9
Year of publication
1995
Pages
1145 - 1152
Database
ISI
SICI code
0006-2979(1995)60:9<1145:LCOCRT>2.0.ZU;2-Z
Abstract
Earlier it was reported that the recoupling action of cyclosporin A on rat liver mitochondria that have undergone the Ca2+-dependent permeab ility transition required higher cyclosporin A concentrations than tho se preventing the permeabilization as well as additional effectors suc h as adenine nucleotides or Mg2+. Here we present data showing that cy closporin A reseals the permeability transition pore and prevents its opening at the same concentrations (as low as 0.1-0.4 mu M), although higher concentrations (0.5-1 mu M) are required for recoupling of the mitochondria. In contrast to recoupling of mitochondria, resealing of the pore by cyclosporin A does not require Mg2+ or adenine nucleotides . Moreover, carboxyatractylate, which reverses the cyclosporin A-induc ed restoration of the membrane potential, does not open the permeabili ty transition pore again. Carboxyatractylate-induced depolarization of the mitochondrial inner membrane is sensitive to ruthenium red as wel l as to EGTA. Also, ruthenium red restores the recoupling action of cy closporin A in the absence of carboxyatractylate. These data suggest t hat loss of recoupling potency of cyclosporin. These data suggest that loss of recoupling action of cyclosporin A may result from induction of a Ca2+/2H(+)-antiporter. Induction of the Ca2+/2H(+)-antiporter in combination with the ruthenium red-sensitive Ca2+ uniporter provides m itochondria completely without pore opening. The induction of the Ca2/2H(+)-antiporter apparently results from inhibition of the ADP/ATP-an tiporter by a natural or exogenous inhibitor. This process seems to re quire preliminary loss of some protecting factors from the mitochondri al matrix.