The nephrotoxic metal cadmium (Cd²⁺) causes mitochondrial damage and apoptosis of kidney proximal tubule cells. A potassium cycle involving a K⁺ uniporter and a K⁺/H⁺ exchanger in the inner mitochondrial membrane (IMM) is thought to contribute to the maintenance of the structural and functional integrity of mitochondria. Here we have investigated the effect of Cd²⁺ on K⁺ cycling in rat kidney cortex mitochondria. Cd²⁺ (EC₅₀ ~19 µM) induced swelling of non-energized mitochondria suspended in isotonic salt solutions according to the sequence KCl = NaCl > LiCl >> choline-Cl. Cd²⁺-induced swelling of energized mitochondria had a similar EC₅₀ and showed the same cation dependence but was followed by a spontaneous contraction. Mitochondrial Ca²⁺ uniporter (MCU) blockers abolished swelling, while permeability transition pore inhibitors had no effect. This suggests the need for Cd²⁺ influx through the MCU for swelling to occur. Complete loss of mitochondrial membrane potential (_m) induced by K⁺ influx did not affect contraction, but addition of the K⁺/H⁺ exchanger blocker, quinine (1 mM), or of the electroneutral protonophore, nigericin (0.4 µM), abolished contraction suggesting that mitochondrial pH gradient (pH_m) drives contraction. Accordingly, a quinine-inhibitable partial dissipation of mitochondrial pH gradient (pH_m) coincided with the swelling-contraction phase. The data indicate that Cd²⁺ enters the matrix through the MCU to activate a K⁺ cycle. Initial K⁺ load via a Cd²⁺-activated K⁺ uniporter in the IMM causes osmotic swelling, breakdown of _m and triggers quinine-sensitive K⁺/H⁺ exchange and contraction. Thus Cd²⁺-induced activation of a K⁺ cycle contributes to dissipation of the mitochondrial protonmotive force.