Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.11889/7850
Title: Very long chain ceramides interfere with C16-ceramide-induced channel formation: A plausible mechanism for regulating the initiation of intrinsic apoptosis
Authors: Stiban, J. 
Perera, M. 
Keywords: Ceramides;Bioactive compounds;Sphingolipidoses;Sphingolipids - Metabolism;Very long chain fatty acid;Ceramide channel;Mitochondrial pathology;Mitochondrial apoptosis;Cytochrome c release
Issue Date: 2015
Publisher: Biochimica et Biophysica Acta - Biomembranes
Abstract: Mitochondria mediate both cell survival and death. The intrinsic apoptotic pathway is initiated by the permeabilization of the mitochondrial outer membrane to pro-apoptotic inter-membrane space (IMS) proteins. Many pathways cause the egress of IMS proteins. Of particular interest is the ability of ceramide to self assemble into dynamic water-filled channels. The formation of ceramide channels is regulated extensively by Bcl-2 family proteins and dihydroceramide. Here, we show that the chain length of biologically active ceramides serves as an important regulatory factor. Ceramides are synthesized by a family of six mammalian ceramide synthases (CerS) each of which produces a subset of ceramides that differ in their fatty acyl chain length. Various ceramides permeabilize mitochondria differentially. Interestingly, the presence of very long chain ceramides reduces the potency of C16-mediated mitochondrial permeabilization indicating that the intercalation of the lipids in the dynamic channel has a destabilizing effect, reminiscent of dihydroceramide inhibition of ceramide channel formation (Stiban et al., 2006).Moreover, mitochondria isolated from cells overexpressing the ceramide synthase responsible for the production of C16-ceramide (CerS5) are permeabilized faster upon the exogenous addition of C16-ceramide whereas they are resistant to permeabilization with added C24-ceramide. On the other hand mitochondria isolated from CerS2-overexpressing cells show the opposite pattern, indicating that the product of CerS2 inhibits C16-channel formation ex vivo and vice versa. This interplay between different ceramide metabolic enzymes and their products adds a new dimension to the complexity of mitochondrial-mediated apoptosis, and emphasizes its role as a key regulatory step that commits cells to life or death.
URI: http://hdl.handle.net/20.500.11889/7850
DOI: 10.1016/j.bbamem.2014.11.018
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