Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation
Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation
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DOI：
10.1074/jbc.c800132200
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发表时间：
2008-09-26
影响因子：
4.8
通讯作者：
Bernardi, Paolo
中科院分区：
文献类型：
--
作者：
Basso, Emy;Petronilli, Valeria;Bernardi, Paolo
无论渗透阴离子是磷酸盐、砷酸盐还是钒酸盐，充满活力的小鼠肝脏线粒体都显示出相同的钙保留能力（一种敏感的渗透性过渡孔（PTP）打开倾向的测量方法）。然而，出乎意料的是，磷酸是环孢素A （CsA）或亲环蛋白D （CyP-D）基因失活对PTP脱敏的特异性要求。事实上，当磷酸盐被砷酸盐、钒酸盐或碳酸氢盐取代时，CsA和cypd消融对PTP的抑制作用消失了。在砷酸盐或钒酸盐存在但不存在磷酸盐的情况下，加载相同量的Ca2+后，野生型小鼠、无cypd小鼠和CsA处理的野生型小鼠的线粒体中PTP对各种诱导剂的敏感性相同。这些发现要求对基于CsA或cypd消融作用的PTP在细胞死亡中的作用的结论进行重新评估。
Energized mouse liver mitochondria displayed the same calcium retention capacity (a sensitive measure of the propensity of the permeability transition pore (PTP) to open) irrespective of whether phosphate, arsenate, or vanadate was the permeating anion. Unexpectedly, however, phosphate was specifically required for PTP desensitization by cyclosporin A (CsA) or by genetic inactivation of cyclophilin D (CyP-D). Indeed, when phosphate was replaced by arsenate, vanadate, or bicarbonate, the inhibitory effects of CsA and of CyP-D ablation on the PTP disappeared. After loading with the same amount of Ca2+ in the presence of arsenate or vanadate but in the absence of phosphate, the sensitivity of the PTP to a variety of inducers was identical in mitochondria from wild-type mice, CyP-D-null mice, and wild-type mice treated with CsA. These findings call for a reassessment of conclusions on the role of the PTP in cell death that are based on the effects of CsA or of CyP-D ablation.