CA2+ DEPLETION PREVENTS ANOXIC DEATH OF HEPATOCYTES BY INHIBITING MITOCHONDRIAL PERMEABILITY TRANSITION

被引:81
作者
PASTORINO, JG [1 ]
SNYDER, JW [1 ]
HOEK, JB [1 ]
FARBER, JL [1 ]
机构
[1] THOMAS JEFFERSON UNIV, DEPT PATHOL, PHILADELPHIA, PA 19107 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 1995年 / 268卷 / 03期
关键词
CYCLOSPORINE A; ROTENONE; CYANIDE; 1,2-BIS(2-AMINOPHENOXY)-ETHANE-N,N,N,N-TETRAACETIC ACID-ACETOXYMETHYL ESTER;
D O I
10.1152/ajpcell.1995.268.3.C676
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 [H-3]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+.
引用
收藏
页码:C676 / C685
页数:10
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