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J. Biol. Chem., Vol. 282, Issue 35, 25940-25949, August 31, 2007

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JNK3 Signaling Pathway Activates Ceramide Synthase Leading to Mitochondrial Dysfunction^*

Jin Yu, Sergei A. Novgorodov, Daria Chudakova, Hong Zhu, Alicja Bielawska^¶, Jacek Bielawski^¶, Lina M. Obeid^||, Mark S. Kindy^||, and Tatyana I. Gudz^||1

From the ^||Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401 and the Departments of Neuroscience, Medicine, and ^¶Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425

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.

Received for publication, March 1, 2007 , and in revised form, June 1, 2007.

^* This work was supported by the NCCR COBRE in Lipidomics and Pathobiology Grant P20 RR 17677-04 (to T. I. G.) from the National Institutes of Health, Veterans Affairs Merit awards (to T. I. G., L. M. O., and M. S. K.), and National Institutes of Health Grant AG16583 (to L. M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neuroscience, Medical University of South Carolina, 114 Doughty St., Charleston, SC 29425. Tel.: 843-792-6439; Fax: 843-876-5099; E-mail: gudz{at}musc.edu.

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