Inhibition by cyclosporine A of the prooxidant-induced but not of the sodium-induced calcium release from rat kidney mitochondria

Abstract

The use of the immunosuppressive drug cyclosporine A (CSA) is restricted by its nephrotoxicity. Perturbation of Ca 2+ homeostasis has been implicated in chemical toxicity. Mitochondria, a key regulator of Ca 2+ homeostasis, may be a target of the drug. Here we show that CSA inhibits at low concentrations the prooxidant-induced but not the sodium-induced Ca 2+ release from rat kidney mitochondria. CSA does not affect Ca 2+ uptake by mitochondria. Inhibition of Ca 2+ release is due to inhibition of intramitochondrial enzymatic hydrolysis of NAD + to ADP-ribose and nicotinamide. These findings suggest a very specific effect of CSA on mitochondrial Ca 2+ release by which the drug interferes with cellular Ca 2+ homeostasis. This is possibly the basis of CSA nephrotoxicity.