Ceramide Biogenesis Is Required for Radiation-Induced Apoptosis in the Germ Line of C. elegans

Abstract

Ceramide engagement in apoptotic pathways has been a topic of controversy. To address this controversy, we tested loss-of-function (lf) mutants of conserved genes of sphingolipid metabolism in Caenorhabditis elegans. Although somatic (developmental) apoptosis was unaffected, ionizing radiation-induced apoptosis of germ cells was obliterated upon inactivation of ceramide synthase and restored upon microinjection of long-chain natural ceramide. Radiation-induced increase in the concentration of ceramide localized to mitochondria and was required for BH3-domain protein EGL-1-mediated displacement of CED-4 (an APAF-1-like protein) from the CED-9 (a Bcl-2 family member)/CED-4 complex, an obligate step in activation of the CED-3 caspase. These studies define CEP-1 (the worm homolog of the tumor suppressor p53)-mediated accumulation of EGL-1 and ceramide synthase-mediated generation of ceramide through parallel pathways that integrate at mitochondrial membranes to regulate stress-induced apoptosis.

Germ Cell Apoptosis and DNA Damage Responses

“…Some reports suggest that ceramides can form channels in mitochondrial outer membranes and promote the release of pro-apoptotic factors, an obligate step in mammalian apoptosis execution. In worms, mutations blocking ceramide biogenesis completely abrogate IR-induced apoptosis and this defect appears to be rescued by micro-injecting long-chain ceramides into the worm gonad, and evidence was provided that ceramide might accumulate upon apoptosis induction (Deng et al 2008 ) (Fig. 9.2 ).…”

“…This assumption is likely to be an oversimpli fi cation, especially when it comes to apoptosis induction (Deng et al 2008 ) . Ceramide is a central molecule in sphingolipid metabolism and critical for plasma membrane integrity.…”

Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans

“…Using the clozapine-induced developmental delay/lethality model and the inhibition of pharyngeal pumping phenotypes, we analyzed over 10 mutants of genes centered on ceramide metabolism and discovered that enzymes that impact upon GlcCer levels mediate some of effects of clozapine. These findings were made possible by use of C. elegans, which has many available mutants (Deng et al, 2008). Analysis of a single gene mutant (eg, only sms-1), in a complex metabolic network, may not reveal the key molecules responsible for the disease.…”

“…Compared with that of wild-type strains, the number of puncta formed in the cgt-3(tm504) mutants was Clozapine modulates GlcCer and protein aggregates L Hao et al Figure 2 Glucosylceramide (GlcCer) mediates clozapine-induced developmental delay/lethality and inhibition of pharyngeal pumping. The sphingolipid (SL) metabolic pathways conserved from yeast to humans is shown (Deng et al, 2008;Griffitts et al, 2005). Enzymes in red indicates hypersensitive to clozapine, blue indicates resistant to clozapine and black indicates the same as wild type.…”

“…The first antipsychotic drugs (APDs) were discovered in the 1950s (Deng et al, 2008;Lieberman et al, 2008). Clinically, the direct mechanism of action of these drugs has been thought to be full or partial antagonism of monoamine receptors, especially dopamine D2 and serotonin receptors, the blockade of which leads, directly and indirectly, to widespread alterations in neuroconnectivity and neurotransmission (Brunello et al, 1995).…”