Ca2+ depletion prevents anoxic death of hepatocytes by inhibiting mitochondrial permeability transition
- 1 March 1995
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 268 (3), C676-C685
- https://doi.org/10.1152/ajpcell.1995.268.3.c676
Abstract
Removal of Ca2+ from the culture medium or treatment with the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) prevented the killing of rat hepatocytes by anoxia and rotenone, but not by cyanide. Neither manipulation prevented the loss of the mitochondrial membrane potential or the depletion of ATP. A mitochondrial permeability transition (MPT) was demonstrated in digitonin-permeabilized hepatocytes as an increased [3H]sucrose-accessible space sensitive to cyclosporin A (CyA). Ca2+ depletion by either means prevented the MPT measured in intact cells made anoxic or treated with rotenone. In isolated mitochondria deenergized by rotenone, BAPTA-AM prevented the MPT induced by palmitoyl CoA. By contrast, in isolated mitochondria deenergized by cyanide, BAPTA-AM alone did not prevent the MPT. Rather, BAPTA-AM plus CyA were required. Similarly, the killing of cultured hepatocytes by cyanide was prevented by BAPTA-AM plus CyA, but not by either agent alone. The MPT in intact cells treated with cyanide was also prevented by BAPTA-AM plus CyA. These data define a specific requirement for Ca2+ in the killing of hepatocytes that follows the inhibition of electron transport. A model is presented in which the MPT depends on factors that modulate the sensitivity of the permeability transition to the matrix concentration of Ca2+.Keywords
This publication has 9 references indexed in Scilit:
- Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorinNature, 1992
- On the thyroid hormone-induced increase in respiratory capacity of isolated rat hepatocytesBiochimica et Biophysica Acta (BBA) - Bioenergetics, 1991
- Transient induction of the mitochondrial permeability transition by uncoupler plus a Ca2+-specific chelatorBiochimica et Biophysica Acta (BBA) - Bioenergetics, 1991
- Cyclosporin A-sensitive and insensitive mechanisms produce the permeability transition in mitochondriaBiochemical and Biophysical Research Communications, 1989
- Mitochondrial damage as a mechanism of cell injury in the killing of cultured hepatocytes by tert-butyl hydroperoxideArchives of Biochemistry and Biophysics, 1989
- The reversible Ca2+-induced permeabilization of rat liver mitochondriaBiochemical Journal, 1986
- Measurement of protein using bicinchoninic acidAnalytical Biochemistry, 1985
- Accelerated phospholipid degradation in anoxic rat hepatocytesArchives of Biochemistry and Biophysics, 1981
- Chapter 4 Preparation of Isolated Rat Liver CellsMethods in cell biology, 1976