title: 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.
authors: Institute of Anatomy, University of Bern, Bern, Switzerland.
authors: Eduard B
authors: EB
authors: Babiychuk
authors: Alexander P
authors: AP
authors: Atanassoff
authors: Katia
authors: K
authors: Monastyrskaya
authors: Christina
authors: C
authors: Brandenberger
authors: Daniel
authors: D
authors: Studer
authors: Catherine
authors: C
authors: Allemann
authors: Annette
authors: A
authors: Draeger
mesh_terms: D017305:Annexin A1 / Q000378:metabolism; D017306:Annexin A2 / Q000378:metabolism; D017209:Apoptosis; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*
chemical_list: C472822:ANXA2 protein, human; D017305:Annexin A1; D017306:Annexin A2; D002518:Ceramides