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