Very long chain ceramides interfere with C16-ceramide-induced channel formation: A plausible mechanism for regulating the initiation of intrinsic apoptosis

Biochim Biophys Acta. 2015 Feb;1848(2):561-7. doi: 10.1016/j.bbamem.2014.11.018. Epub 2014 Nov 21.


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.

Keywords: Ceramide channel; Cytochrome c release; Mitochondrial apoptosis; Sphingolipid; Very long chain fatty acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / genetics
  • Adenylate Kinase / metabolism
  • Animals
  • Apoptosis / drug effects*
  • Cell Survival / drug effects
  • Ceramides / chemistry*
  • Ceramides / metabolism
  • Ceramides / pharmacology
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Liposomes / chemistry*
  • Liposomes / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mitochondria / chemistry
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Membranes / chemistry
  • Mitochondrial Membranes / drug effects*
  • Mitochondrial Membranes / metabolism
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Rats, Sprague-Dawley
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sphingosine N-Acyltransferase / genetics
  • Sphingosine N-Acyltransferase / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • Ceramides
  • Liposomes
  • Membrane Proteins
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Oxidoreductases
  • dihydroceramide desaturase
  • CERS2 protein, human
  • CERS5 protein, human
  • Sphingosine N-Acyltransferase
  • Adenylate Kinase