Siskind Leah J, Fluss Sharon, Bui Minh, Colombini Marco
Department of Biology, University of Maryland College Park, College Park, Maryland, USA.
J Bioenerg Biomembr. 2005 Aug;37(4):227-36. doi: 10.1007/s10863-005-6632-2.
Ceramide channels formed in the outer membrane of mitochondria have been proposed to be the pathways by which proapoptotic proteins are released from mitochondria during the early stages of apoptosis. We report that sphingosine also forms channels in membranes, but these differ greatly from the large oligomeric barrel-stave channels formed by ceramide. Sphingosine channels have short open lifetimes and have diameters less than 2 nm, whereas ceramide channels have long open lifetimes, enlarge in size reaching diameters in excess of 10 nm. Unlike ceramide, sphingosine forms channels in erythrocyte plasma membranes that vary in size with concentration, but with a maximum possible channel diameter of 2 nm. In isolated mitochondria, a large proportion of the added sphingosine was rapidly metabolized to ceramide in the absence of externally added fatty acids or fatty-acyl-CoAs. The ceramide synthase inhibitor, fumonisin B1 failed to prevent sphingosine metabolism to ceramide and actually increased it. However, partial inhibition of conversion to ceramide was achieved in the presence of ceramidase inhibitors, indicating that reverse ceramidase activity is at least partially responsible for sphingosine metabolism to ceramide. A small amount of cytochrome c release was detected. It correlated with the level of ceramide converted from sphingosine. Thus, sphingosine channels, unlike ceramide channels, are not large enough to allow the passage of proapoptotic proteins from the intermembrane space of mitochondria to the cytoplasm.
线粒体外膜中形成的神经酰胺通道被认为是凋亡早期促凋亡蛋白从线粒体释放的途径。我们报告，鞘氨醇也能在膜中形成通道，但这些通道与神经酰胺形成的大型寡聚桶状通道有很大不同。鞘氨醇通道的开放寿命短，直径小于2纳米，而神经酰胺通道的开放寿命长，尺寸会增大，直径超过10纳米。与神经酰胺不同，鞘氨醇在红细胞质膜中形成的通道大小随浓度变化，但最大可能通道直径为2纳米。在分离的线粒体中，在没有外部添加脂肪酸或脂肪酰辅酶A的情况下，大部分添加的鞘氨醇会迅速代谢为神经酰胺。神经酰胺合酶抑制剂伏马菌素B1未能阻止鞘氨醇代谢为神经酰胺，实际上还增加了这种代谢。然而，在存在神经酰胺酶抑制剂的情况下，实现了对转化为神经酰胺的部分抑制，表明反向神经酰胺酶活性至少部分负责鞘氨醇代谢为神经酰胺。检测到少量细胞色素c释放。它与从鞘氨醇转化而来的神经酰胺水平相关。因此，与神经酰胺通道不同，鞘氨醇通道不够大，无法允许促凋亡蛋白从线粒体膜间隙进入细胞质。
