Cyclophilin-D is a peptidylprolyl cis–trans isomerase of the mitochondrial matrix. It is involved in mitochondrial permeability transition, in which the adenine nucleotide translocase of the inner membrane is transformed from an antiporter to a non-selective pore. The permeability transition has been widely considered as a mechanism in both apoptosis and necrosis. The present study examines the effects of cyclophilin-D on the permeability transition and lethal cell injury, using a neuronal (B50) cell line stably overexpressing cyclophilin-D in mitochondria. Cyclophilin-D overexpression rendered isolated mitochondria far more susceptible to the permeability transition induced by Ca2+ and oxidative stress. Similarly, cyclophilin-D overexpression brought forward the onset of the permeability transition in intact cells subjected to oxidative stress. In addition, in the absence of stress, the mitochondria of cells overexpressing cyclophilin-D maintained a lower inner-membrane potential than those of normal cells. All these effects of cyclophilin-D overexpression were abolished by cyclosporin A. It is concluded that cyclophilin-D promotes the permeability transition in B50 cells. However, cyclophilin-D overexpression had opposite effects on apoptosis and necrosis; whereas NO-induced necrosis was promoted, NO- and staurosporine-induced apoptosis were inhibited. These findings indicate that the permeability transition leads to cell necrosis, but argue against its involvement in apoptosis.
Complex Contribution of Cyclophilin D to Ca2+-induced Permeability Transition in Brain Mitochondria, with Relation to the Bioenergetic State
