Protection of C. elegans from Anoxia by HYL-2 Ceramide Synthase

Abstract

Oxygen deprivation is rapidly deleterious for most organisms. However, Caenorhabditis elegans has developed the ability to survive anoxia for at least 48 hours. Mutations in the DAF-2/DAF-16 insulin-like signaling pathway promote such survival. We describe a pathway involving the HYL-2 ceramide synthase that acts independently of DAF-2. Loss of the ceramide synthase gene hyl-2 results in increased sensitivity of C. elegans to anoxia. C. elegans has two ceramide synthases, hyl-1 and hyl-2, that participate in ceramide biogenesis and affect its ability to survive anoxic conditions. In contrast to hyl-2(lf) mutants, hyl-1(lf) mutants are more resistant to anoxia than normal animals. HYL-1 and HYL-2 have complementary specificities for fatty acyl chains. These data indicate that specific ceramides produced by HYL-2 confer resistance to anoxia.

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

“…Thus, the elongase enzymes and ceramide synthases provide a major source of structural diversity among sphingolipids. Importantly, these structural differences give rise to distinct functions, as exemplified by chain-length-specific roles for sphingolipids in the response to anoxia in Caenorhabditis elegans (Menuz et al 2009) and in the barrier function of skin (Feingold 2009).…”

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

“…Total lipid and SLs were extracted and were adapted from Menuz et al (2009). The bacterial or worm samples (~0.3 ml) were ground in a mortar immersed in a dry ice and ethanol.…”

Non‐apoptotic cell death in Caenorhabditis elegans

“…elegans has been shown to survive for at least 48 hr under anoxic conditions. Prolonged anoxia causes necrosis in all tissues of the worm, evident by the accumulation of propidium iodide-stained necrotic cells (Menuz et al, 2009). Specific daf-2 mutants are highly resistant to long-term anoxia, and this resistance is mediated by two glycolytic enzymes (glyceraldehyde-3-phosphate dehydrogenases) encoded by the genes gpd-2 and gpd-3 (Mendenhall et al, 2006).…”

“…Ceramides have also been shown to function as proapoptotic molecules following hypoxia or ischemia (Basnakian et al, 2005;Novgorodov and Gudz, 2009). Loss-of-function mutations in the hyl-1 and hyl-2 genes have opposite effects on anoxia sensitivity (Menuz et al, 2009). While hyl-2(lf) mutants are anoxia sensitive, hyl-1(lf) mutants are anoxia resistant.…”

“…These findings are consistent with studies in primates implicating an analogous calpain-cathepsin axis in the execution of necrotic cell death following ischemic episodes and stroke (Yamashima, 2000(Yamashima, , 2004. (Scott et al, 2002) Anoxic treatment Oxygen/energy limitation Cells throughout the whole body (Menuz et al, 2009) Chemical inhibitors of the respiratory chain (sodium azide)…”