The targeting of plasmalemmal ceramide to mitochondria during apoptosis

Abstract

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.

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

“…Both pathways are thought to be interlinked and converge on the mitochondria, whose outer membranes become increasingly permeable. 49 This increase in the permeability of the mitochondrial outer membrane causes proteins to leak out from the intermembranous space, activation of caspase-3 and DNases, and finally apoptosis. Given that we found increased caspase 3 activity in the Cat E, we focused on the mitochondrial pathway.…”

Complement Activation by Ceramide Transporter Proteins

“…Furthermore, both CERT and CERT L bind and transport ceramide. Ceramide levels are tightly regulated in the cell, and changes in ceramide levels or localization are associated with apoptosis (34)(35)(36). For example, extracellularly oriented ceramide is generated during apoptosis via the sphingomyelinase pathway (37,38) and the de novo synthesis pathway (39).…”

Delivery of long chain C16 and C24 ceramide in HeLa cells using oxidized graphene nanoribbons

“…Of all the sphingolipids, ceramide has been revealed as one of the most biologically active, with important roles in a number of processes including cell growth and proliferation, cell senescence, differentiation, apoptosis, necrosis, and autophagy (Adam, Heinrich, Kabelitz, & Schutze, ; Hetz et al, ; Obeid, Linardic, Karolak, & Hannun, ; Okazaki, Bell, & Hannun, ; Pattingre, Bauvy, Levade, Levine, & Codogno, ; Venable, Lee, Smyth, Bielawska, & Obeid, ; Zou, Stern, & Sun, ). Apoptosis in particular has been shown to have many ceramide‐dependent mechanisms in both the extrinsic pathway mediated by death ligands (Brenner et al, ; Cremesti et al, ; Donato & Klostergaard, ; Dumitru & Gulbins, ; Elojeimy et al, ; Higuchi, Singh, Jaffrezou, & Aggarwal, ; Huang, Yang, Chen, & Pang, ; Karasavvas & Zakeri, ; Nam, Amoscato, & Lee, ; Sawada et al, ; White‐Gilbertson et al, ; Yoon et al, ) and the intrinsic pathway mediated by mitochondrial outer membrane permeabilization (Babiychuk et al, ; Bionda, Portoukalian, Schmitt, Rodriguez‐Lafrasse, & Ardail, ; Birbes, El Bawab, Hannun, & Obeid, ; Lin et al, ; Luo, Budihardjo, Zou, Slaughter, & Wang, ; Morales et al, ; Stiban, Caputo, & Colombini, ; Yuan, Williams, Adachi, Oltersdorf, & Gottlieb, ). Ceramide has also been shown to be an important part of the metabolism of many types of cancers (Morad & Cabot, ).…”