Stiban 2014 Abstract MiP2014
|Very long chain ceramides interfere with C16 ceramide-induced channel formation: rheostatic control of apoptosis.|
Mitochondria mediate both cell survival and cell death. The intrinsic apoptotic pathway is initiated by the permeabilization of the mitochondrial outer membrane to pro-apoptotic intermembrane space proteins, such as cytochrome c. A number of pathways are known to cause the egress of mitochondrial intermembrane space (mtIMS) proteins. Of particular interest is the ability of the lipid, ceramide, to self-assemble into dynamic water-filled channels. The formation of ceramide channels is regulated extensively by Bcl-2 family proteins as well as dihydroceramide, the immediate precursor in the de novo ceramide biosynthetic pathway. Here, we present evidence that the chain length of biological 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. Indeed, we find that various ceramides function to permeabilize mitochondria differentially. Interestingly, the presence of very long chain ceramides reduces the potency of C16-mediated permeabilization of mitochondria, indicating that the intercalation of the lipids in the dynamic channel is destabilizing, reminiscent of dihydroceramide inhibition of ceramide channel formation . Moreover, cells overexpressing the ceramide synthase responsible for the production of C16-ceramide (CerS5) are more vulnerable to etoposide, compared to cells overexpressing CerS2 (very long chain fatty acyl ceramides). We also find that co-overexpression of CerS2 and CerS5 reduces the fraction of dead cells upon etoposide treatment, indicating that the product of CerS2 inhibits C16-channel formation in vivo. This interplay between different ceramide metabolic enzymes and their products adds a new dimension to the complexity of mitochondrial-mediated apoptosis and emphasizes its importance as a key regulatory step that commits cells to life or death.
Labels: MiParea: mt-Membrane
Event: C4, Oral MiP2014: ceramide
1-Dep Biol Biochem, Birzeit Univ, Palestine; 2-Dep Biol, Univ Maryland, College Park, MD, USA. - [email protected]
- Stiban J, Fistere D, Colombini M (2006) Dihydroceramide hinders ceramide channel formation: implications on apoptosis. Apoptosis 11: 773-80.