Siskind Leah J, Kolesnick Richard N, Colombini Marco
Department of Biology, University of Maryland, College Park, MD 20742, USA.
Mitochondrion. 2006 Jun;6(3):118-25. doi: 10.1016/j.mito.2006.03.002. Epub 2006 Mar 29.
Recent evidence suggests that the ability of ceramides to induce apoptosis is due to a direct action on mitochondria. Mitochondria are known to contain enzymes responsible for ceramide synthesis and hydrolysis and mitochondrial ceramide levels have been shown to be elevated prior to the mitochondrial phase of apoptosis. Ceramides have been reported to induce the release of intermembrane space proteins from mitochondria, which has been linked to their ability to form large channels in membranes. The aim of this study was to determine if the membrane concentration of ceramide required for the formation of protein permeable channels is within the range that is present in mitochondria during the induction phase of apoptosis. Only a very small percentage of the ceramide actually inserts into the mitochondrial membranes. The permeability of the mitochondrial outer membrane correlates directly with the level of ceramide in the membrane. Importantly, the concentration of ceramide at which significant channel formation occurs is consistent with the level of mitochondrial ceramide that occurs during the induction phase of apoptosis (4 pmol ceramide/nanomole phospholipid). Similar results were obtained with short- and long-chain ceramide. Ceramide channel formation is specific to mitochondrial membranes in that no channel formation occurs in the plasma membranes of erythrocytes even at concentrations 20 times higher than those required for channel formation in mitochondrial outer membranes. Thus, ceramide channels are good candidates for the pathway by which proapoptotic proteins are released from mitochondria during the induction phase of apoptosis.
最近的证据表明，神经酰胺诱导细胞凋亡的能力源于其对线粒体的直接作用。已知线粒体含有负责神经酰胺合成和水解的酶，并且在线粒体凋亡阶段之前，线粒体神经酰胺水平已被证明会升高。据报道，神经酰胺可诱导线粒体膜间隙蛋白的释放，这与其在膜中形成大通道的能力有关。本研究的目的是确定在凋亡诱导阶段线粒体中存在的神经酰胺浓度范围内，是否能形成蛋白质可通透的通道。实际上，只有极小比例的神经酰胺插入线粒体膜。线粒体外膜的通透性与膜中神经酰胺的水平直接相关。重要的是，发生显著通道形成时的神经酰胺浓度与凋亡诱导阶段线粒体中出现的神经酰胺水平一致（4皮摩尔神经酰胺/纳摩尔磷脂）。短链和长链神经酰胺也得到了类似的结果。神经酰胺通道形成对线粒体膜具有特异性，因为即使红细胞质膜中的神经酰胺浓度比线粒体外膜形成通道所需浓度高20倍，也不会形成通道。因此，在凋亡诱导阶段，神经酰胺通道很可能是促凋亡蛋白从线粒体释放的途径。
