Arachidonic acid causes cell death through the mitochondrial permeability transition -: Implications for tumor necrosis factor-α apoptotic signaling
Arachidonic acid causes cell death through the mitochondrial permeability transition -: Implications for tumor necrosis factor-α apoptotic signaling
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DOI：
10.1074/jbc.m010603200
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发表时间：
2001-04-13
影响因子：
4.8
通讯作者：
Bernardi, P
中科院分区：
文献类型：
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作者：
Scorrano, L;Penzo, D;Bernardi, P
我们研究了花生四烯酸和棕榈酸在离体大鼠肝线粒体和大鼠肝癌MH1C1细胞中的作用。我们发现，这两种化合物诱导线粒体通透性转换（PT）。然而，与棕榈酸不同，花生四烯酸在不引起PT独立去极化或呼吸抑制的浓度下引起PT，这表明对PT孔有特定作用。当添加到完整的MH1C1细胞，花生四烯酸，但不是棕榈酸引起的线粒体PT原位伴随细胞色素c的释放，并迅速随后细胞死亡。花生四烯酸的上述作用均能被环孢菌素A阻断，但不能被磷脂酶A（2）抑制剂马兜铃酸阻断。相反，肿瘤坏死因子α引起磷脂水解，诱导PT，细胞色素c释放和细胞死亡，可以抑制环孢菌素A和马兜铃酸。这些发现表明，由胞质磷脂酶A（2）产生的花生四烯酸可能是通过诱导线粒体PT而在原位介导肿瘤坏死因子α细胞毒性的介质。
We have investigated the effects of arachidonic and palmitic acids in isolated rat liver mitochondria and in rat hepatoma MH1C1 cells. We show that both compounds induce the mitochondrial permeability transition (PT). At variance from palmitic acid, however, arachidonic acid causes a PT at concentrations that do not cause PT-independent depolarization or respiratory inhibition, suggesting a specific effect on the PT pore. When added to intact MH1C1 cells, arachidonic acid but not palmitic acid caused a mitochondrial PT in situ that was accompanied by cytochrome c release and rapidly followed by cell death. All these effects of arachidonic acid could be prevented by cyclosporin A but not by the phospholipase A(2) inhibitor aristolochic acid. In contrast, tumor necrosis factor alpha caused phospholipid hydrolysis, induction of the PT, cytochrome c release, and cell death that could be inhibited by both cyclosporin A and aristolochic acid. These findings suggest that arachidonic acid produced by cytosolic phospholipase A(2) may be a mediator of tumor necrosis factor alpha cytotoxicity in situ through induction of the mitochondrial PT.