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J. Biol. Chem., Vol. 278, Issue 15, 13294-13301, April 11, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/15/13294    most recent M208670200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pias, E. K. Articles by Aw, T. Y. Search for Related Content PubMed PubMed Citation Articles by Pias, E. K. Articles by Aw, T. Y. Social Bookmarking                      What's this?

Differential Effects of Superoxide Dismutase Isoform Expression on Hydroperoxide-induced Apoptosis in PC-12 Cells^*

Erin K. Pias, Oleksandr Y. Ekshyyan, Carol A. Rhoads, John Fuseler, Lynn Harrison, and Tak Yee Aw^§

From the Departments of Molecular and Cellular Physiology and  Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932

The current study examines the contribution of mitochondria-derived reactive oxygen species (ROS) in tert-butyl-hydroperoxide (TBH)-induced apoptotic signaling using clones of undifferentiated pheochromocytoma (PC-12) cells that stably overexpress the human mitochondrial or cytoplasmic forms of superoxide dismutase (SOD) (viz. Mn-SOD or CuZn-SOD, respectively). Exposure of wild type cells to TBH caused an early generation of ROS (30 min) that resulted in cell apoptosis at 24 h. These responses were attenuated with N-acetylcysteine pretreatment; however, N-acetylcysteine was ineffective in cytoprotection when added after TBH-induced ROS formation. Stable overexpression of SOD isoforms caused a 2- and 3.5-fold elevation in CuZn-SOD and Mn-SOD activities in the cytoplasm and mitochondria, respectively, and 3-fold increases in cellular GSH content. Accordingly, the stable overexpression of Mn-SOD attenuated TBH-induced mitochondrial ROS generation and cell apoptosis. Whereas transient Mn-SOD expression similarly prevented PC-12 apoptosis, this was associated with increases in SOD activity but not GSH, indicating that cytoprotection by Mn-SOD overexpression is related to mitochondrial ROS elimination and not due to increases in cellular GSH content per se. Stable or transient CuZn-SOD overexpression exacerbated cell apoptosis in conjunction with accelerated caspase-3 activation, regardless of cell GSH levels. Collectively, our results support a role for mitochondrial ROS in TBH-induced PC-12 apoptosis that is attenuated by Mn-SOD overexpression and is independent of cellular GSH levels per se.

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