THE OPERATION OF NA+/CA2+ EXCHANGER PREVENTS INTRACELLULAR CA2+ OVERLOAD AND HEPATOCYTE KILLING FOLLOWING IRON-INDUCED LIPID-PEROXIDATION

Stimulation of lipid peroxidation by incubating isolated rat hepatocytes with ADP/FeCl3 caused a time dependent increase in cytosolic free Ca2+ levels, without influencing cellular Na+ content. Omission of Na+ from the incubation medium greatly increased the accumulation of Ca2+, which was partially reverted upon transferring the cells in a Na+ containing medium. This suggested that a Na+-dependent Ca2+ transporter was activated upon the elevation of cytosolic Ca2+ and partially counteracted the influx of Ca2+ promoted by lipid peroxidation. In the presence of Na+ cell death was not associated with the increase of Ca2+ induced by peroxidative injury; however, decrease of mitochondrial membrane potential and loss of cell viability followed the massive accumulation of Ca2+ occurring in hepatocytes incubated with ADP/FeCl3 in a Na+-free medium. Both these effects were completely prevented by chelation of extracellular Ca2+ with EGTA. Thus, we conclude that Na+-dependent Ca2+ transporter is involved in controlling excessive accumulation of Ca2+ induced by stimulation of lipid peroxidation and can prevent hepatocyte death caused by Ca2+-dependent alterations of mitochondrial activity. (C) 1995 Academic Press, Inc.