Cyclosporin A inhibits thyroid hormone-induced shortening of the tadpole tail through membrane permeability transition.

Regression of the tadpole tail through muscule cell apoptosis is one of the most spectacular events in amphibian metamorphosis. Accumulated evidence has shown that mitochondrial membrane permeability transition (MPT) plays a crucial role in apoptosis. Previously we reported that cyclosporin A (CsA) suppressed 3,5,3'-triiodothyronine (T(3))-induced mitochondrial swelling, which was coupled with cytochrome c (Cyt.c) release through MPT [Comp. Biochem. Phys. 130 (2001) 411-418]. To further clarify the mechanism of tadpole metamorphosis, the present study investigates the effect of CsA on T(3) induced tadpole tail shortening. A low concentration of T(3) (5 x 10(-8) M) was found to induce a shortening of stage X Rana rugosa tadpole tails, accompanied by an increase in caspase-3- and -9 like protease activity, as well as an increase in DNA-fragmentation and ladder formation, while CsA was seen to suppress the effects of T(3). The stage X tadpole tail was found to express Bax mRNA and this expression was not affected by T(3) treatment. CsA, on the other hand, proved to have a slightly supressive effection on Bax expression. 20 microM T(3) as well as 50 microM Ca(2+) induced swelling in mitochondria isolated from the liver of R. rugosa resulting in the release of apoptosis related substances, and the released fraction activated cytosolic caspase-3 and -9 in the presence of dATP. This result indicated that Cyt.c might be released from mitochondria by treatment with T(3) through both direct and indirect action of T(3). From these results and other data it was concluded that mitochondrial MPT plays an important role in T(3)-induced apoptosis in the tadpole tail, resulting in tail shortening, and CsA was seen to suppress the effects of T(3).