Two mechanisms by which ATP depletion potentiates induction of the mitochondrial permeability transition
Two mechanisms by which ATP depletion potentiates induction of the mitochondrial permeability transition
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DOI：
10.1152/ajpcell.1997.273.2.c479
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发表时间：
1997-08-01
影响因子：
5.5
通讯作者：
Farber, JL
中科院分区：
文献类型：
--
作者：
Simbula, G;Glascott, PA;Farber, JL
本研究和以前的研究[J.W.Snyder，J.G.Pastorino，A.M.Attie和J.L.Farber]。上午好。J.Physiol.264(细胞生理学)33)：C709-C714,1993]定义了ATP耗竭促进肝细胞死亡的两种机制。线粒体通透性转变(MPT)与ATP耗竭和细胞死亡密切相关。线粒体失能促进MPT，而ATP通过逆转ATP合酶维持膜电位。随着离子载体A-23187诱导的钙离子内流增加，寡霉素在不损失线粒体膜电位的情况下耗竭细胞内三磷酸腺苷，并进一步升高细胞内钙离子浓度，环孢素A(CyA)可阻止伴随的细胞杀伤。果糖也保存了细胞的活力。随着A-23187对细胞内钙离子浓度的增加，细胞活力由依赖三磷酸腺苷的过程维持。当ATP耗尽时，不能维持钙离子的动态平衡，从而诱发MPT。鱼藤酮也耗尽细胞的三磷酸腺苷，A-23187加速了单独使用鱼藤酮时线粒体膜电位的丧失。CyA和果糖通过鱼藤酮和A-23187阻止细胞杀伤。寡霉素不能阻止果糖的这种作用。我们的结论是，ATP是维持钙稳态所必需的，以防止MPT和由此导致的肝细胞死亡。当电子传递被抑制时，也需要ATP来维持线粒体的能量。
The present and a previous study [J. W. Snyder, J. G. Pastorino, A. M. Attie, and J. L. Farber. Am. J. Physiol. 264 (Cell Physiol. 33): C709-C714, 1993] define two mechanisms whereby ATP depletion promotes liver cell death. ATP depletion and cell death are linked by the mitochondrial permeability transition (MPT). Mitochondrial deenergization promotes the MPT, and ATP maintains a membrane potential by reversal of ATP synthase. With an increased influx of Ca2+ induced by the ionophore A-23187, oligomycin depleted the cells of ATP without loss of the mitochondrial membrane potential and further elevated the intracellular Ca2+ concentration Cyclosporin A (CyA) prevented the accompanying cell killing. Fructose also preserved the viability of the cells. With the increased cytosolic Ca2+ imposed by A-23187, viability is maintained by ATP-dependent processes. Upon depletion of ATP, Ca2+ homeostasis cannot be maintained, and the MPT is induced. Rotenone also depleted the cells of ATP, and A-23187 accelerated the loss of the mitochondrial membrane potential occurring with rotenone alone. CyA and fructose prevented the cell killing with rotenone and A-23187. Oligomycin did not prevent this action of fructose. We conclude that ATP is needed to maintain Ca2+ homeostasis to prevent the MPT and the resultant liver cell death. ATP is also needed to maintain mitochondrial energization when electron transport is inhibited.