title: JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction.
abstract: A cardinal feature of brain tissue injury in stroke is mitochondrial dysfunction leading to cell death, yet remarkably little is known about the mechanisms underlying mitochondrial injury in cerebral ischemia/reperfusion (IR). Ceramide, a naturally occurring membrane sphingolipid, functions as an important second messenger in apoptosis signaling and is generated by de novo synthesis, sphingomyelin hydrolysis, or recycling of sphingolipids. In this study, cerebral IR-induced ceramide elevation resulted from ceramide biosynthesis rather than from hydrolysis of sphingomyelin. Investigation of intracellular sites of ceramide accumulation revealed the elevation of ceramide in mitochondria because of activation of mitochondrial ceramide synthase via post-translational mechanisms. Furthermore, ceramide accumulation appears to cause mitochondrial respiratory chain damage that could be mimicked by exogenously added natural ceramide to mitochondria. The effect of ceramide on mitochondria was somewhat specific; dihydroceramide, a structure closely related to ceramide, did not inflict damage. Stimulation of ceramide biosynthesis seems to be under control of JNK3 signaling: IR-induced ceramide generation and respiratory chain damage was abolished in mitochondria of JNK3-deficient mice, which exhibited reduced infarct volume after IR. These studies suggest that the hallmark of mitochondrial injury in cerebral IR, respiratory chain dysfunction, is caused by the accumulation of ceramide via stimulation of ceramide synthase activity in mitochondria, and that JNK3 has a pivotal role in regulation of ceramide biosynthesis in cerebral IR.
authors.affiliation: Ralph H. Johnson Veterans Affairs Medical Center, and the Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Novgorodov
authors.forename: Daria
authors.initials: D
authors.lastname: Chudakova
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kindy
authors.forename: Tatyana I
authors.initials: TI
authors.lastname: Gudz
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002518:Ceramides / Q000096:biosynthesis* / Q000378:metabolism; D004579:Electron Transport; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology*; D015290:Second Messenger Systems; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D002518:Ceramides; D013109:Sphingomyelins; C109343:dihydroceramide; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D048057:Mitogen-Activated Protein Kinase 10