Cadmium (Cd) is a potent environmental toxic compound that damages the kidney by inducing apoptosis of the proximal tubule cells. The mitochondrion is a pivotal point of the apoptotic pathway because it releases pro-apoptotic factors such as cytochrome c. Using mitochondria isolated by differential centrifugation from rat kidney cortex, we monitored swelling, which is thought to reflect the opening of a mitochondrial permeability transition pore and mitochondrial dysfunction. At Cd concentrations of 5 muM or more, rapid swelling occurred. Moreover, Cd had concentration-dependent effects on swelling induced by the permeability transition pore opener PO(4)(3-): At concentrations of 5 muM or less, PO(4)(3-)-induced swelling was enhanced and cytochrome c release was increased, whereas more than 5 muM Cd significantly inhibited both PO(4)(3-)-induced swelling and cytochrome c release. Thus, Cd may directly interfere with normal mitochondrial function and may also trigger pro-apoptotic pathways in proximal tubule cells in the kidney.