Cd -induced swelling-contraction dynamics in isolated kidney cortex mitochondria: role of Ca uniporter, K cycling, and protonmotive force

Lee, Wing-Kee, Malte Spielmann, Ulrich Bork, and Frank Thévenod. Cd -induced swelling-contraction dynamics in isolated kidney cortex mitochondria: role of Ca uniporter, K cycling, and protonmotive force. Am J Physiol Cell Physiol 289: C656–C664, 2005. First published April 20, 2005; doi:10.1152/ajpcell.00049.2005.—The nephrotoxic metal Cd causes mitochondrial damage and apoptosis of kidney proximal tubule cells. A K 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. In the present study, we have investigated the effect of Cd on K cycling in rat kidney cortex mitochondria. Cd (EC50 19 M) induced swelling of nonenergized mitochondria suspended in isotonic salt solutions according to the sequence KCl NaCl LiCl choline chloride. Cd -induced swelling of energized mitochondria had a similar EC50 value and showed the same cation dependence but was followed by a spontaneous contraction. Mitochondrial Ca uniporter (MCU) blockers, but not permeability transition pore inhibitors, abolished swelling, suggesting the need for Cd influx through the MCU for swelling to occur. Complete loss of mitochondrial membrane potential ( m) induced by K influx did not prevent contraction, but addition of the K /H exchanger blocker, quinine (1 mM), or the electroneutral protonophore nigericin (0.4 M), abolished contraction, suggesting the mitochondrial pH gradient ( pHm) driving contraction. Accordingly, a quinine-sensitive partial dissipation of pHm was coincident with the swelling-contraction phase. The data indicate that Cd enters the matrix through the MCU to activate a K cycle. Initial K load via a Cd -activated K uniporter in the IMM causes osmotic swelling and breakdown of m and triggers quinine-sensitive K /H exchange and contraction. Thus Cd -induced activation of a K cycle contributes to the dissipation of the mitochondrial protonmotive force.