title: Very long chain ceramides interfere with C16-ceramide-induced channel formation: A plausible mechanism for regulating the initiation of intrinsic apoptosis.
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.
authors.affiliation: Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, West Bank 627, Palestine. Electronic address: jstiban@birzeit.edu.
authors.forename: Johnny
authors.initials: J
authors.lastname: Stiban
authors.affiliation: Department of Biology, University of Maryland, College Park, MD 20742, USA. Electronic address: meenunp@gmail.com.
authors.forename: Meenu
authors.initials: M
authors.lastname: Perera
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002518:Ceramides; D008081:Liposomes; D008565:Membrane Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C438311:CERS2 protein, human; C505722:CERS5 protein, human; D051049:Sphingosine N-Acyltransferase; D000263:Adenylate Kinase
keywords: Ceramide channel; Cytochrome c release; Mitochondrial apoptosis; Sphingolipid; Very long chain fatty acid