Institute of Anatomy, University of Bern, Bern, Switzerland.
PLoS One. 2011;6(8):e23706. doi: 10.1371/journal.pone.0023706. Epub 2011 Aug 19.
Ceramide is a key lipid mediator of cellular processes such as differentiation, proliferation, growth arrest and apoptosis. During apoptosis, ceramide is produced within the plasma membrane. Although recent data suggest that the generation of intracellular ceramide increases mitochondrial permeability, the source of mitochondrial ceramide remains unknown. Here, we determine whether a stress-mediated plasmalemmal pool of ceramide might become available to the mitochondria of apoptotic cells. We have previously established annexin A1--a member of a family of Ca(2+) and membrane-binding proteins--to be a marker of ceramide platforms. Using fluorescently tagged annexin A1, we show that, upon its generation within the plasma membrane, ceramide self-associates into platforms that subsequently invaginate and fuse with mitochondria. An accumulation of ceramide within the mitochondria of apoptotic cells was also confirmed using a ceramide-specific antibody. Electron microscopic tomography confirmed that upon the formation of ceramide platforms, the invaginated regions of the plasma membrane extend deep into the cytoplasm forming direct physical contacts with mitochondrial outer membranes. Ceramide might thus be directly transferred from the plasma membrane to the mitochondrial outer membrane. It is conceivable that this "kiss-of-death" increases the permeability of the mitochondrial outer membrane thereby triggering apoptosis.
神经酰胺是细胞过程的关键脂质介质，如分化、增殖、生长停滞和细胞凋亡。在细胞凋亡过程中，神经酰胺在质膜内产生。尽管最近的数据表明细胞内神经酰胺的产生会增加线粒体通透性，但线粒体神经酰胺的来源仍不清楚。在这里，我们确定应激介导的质膜神经酰胺池是否可能提供给凋亡细胞的线粒体。我们之前已经确定 annexin A1（钙和膜结合蛋白家族的成员）是神经酰胺平台的标志物。使用荧光标记的 annexin A1，我们表明，在质膜内生成后，神经酰胺会自组装成平台，随后内陷并与线粒体融合。使用神经酰胺特异性抗体也证实了凋亡细胞中线粒体中神经酰胺的积累。电子显微镜断层扫描证实，在形成神经酰胺平台后，质膜的内陷区域深入细胞质，与线粒体外膜形成直接的物理接触。因此，神经酰胺可能直接从质膜转移到线粒体外膜。可以想象，这种“死亡之吻”增加了线粒体外膜的通透性，从而触发细胞凋亡。
