title: Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain.
abstract: Ceramide is a key intermediate in the pathway of sphingolipid biosynthesis and is an important intracellular messenger. We recently generated a ceramide synthase 2 (CerS2) null mouse that cannot synthesize very long acyl chain (C22-C24) ceramides. This mouse displays severe and progressive hepatopathy. Significant changes were observed in the sphingolipid profile of CerS2 null mouse liver, including elevated C16-ceramide and sphinganine levels in liver and in isolated mitochondrial fractions. Because ceramide may be involved in reactive oxygen species (ROS) formation, we examined whether ROS generation was affected in CerS2 null mice. Levels of a number of anti-oxidant enzymes were elevated, as were lipid peroxidation, protein nitrosylation, and ROS. ROS were generated from mitochondria due to impaired complex IV activity. C16-ceramide, sphingosine, and sphinganine directly inhibited complex IV activity in isolated mitochondria and in mitoplasts, whereas other ceramide species, sphingomyelin, and diacylglycerol were without effect. A fluorescent analog of sphinganine accumulated in mitochondria. Heart mitochondria did not display a substantial alteration in the sphingolipid profile or in complex IV activity. We suggest that C16-ceramide and/or sphinganine induce ROS formation through the modulation of mitochondrial complex IV activity, resulting in chronic oxidative stress. These results are of relevance for understanding modulation of ROS signaling by sphingolipids.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Zigdon
authors.forename: Aviram
authors.initials: A
authors.lastname: Kogot-Levin
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Ruth
authors.initials: R
authors.lastname: Goldschmidt
authors.forename: Samuel
authors.initials: S
authors.lastname: Kelly
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: Avigdor
authors.initials: A
authors.lastname: Scherz
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D004579:Electron Transport; D015227:Lipid Peroxidation; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000473:pathology; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013107:Sphingolipids / Q000737:chemistry; D051049:Sphingosine N-Acyltransferase / Q000235:genetics* / Q000378:metabolism
chemical_list: D002518:Ceramides; D008055:Lipids; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013107:Sphingolipids; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase; D009584:Nitrogen