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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 3, 2005; DOI: 10.1124/jpet.105.088625

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Received for publication April 27, 2005.
Revised June 2, 2005.
Accepted for publication June 2, 2005.

UP-REGULATION OF UCP-2 BY CYANIDE IS LINKED WITH CYTOTOXICITY IN MESENCEPHALIC CELLS

Krishnan Prabhakaran 1, Li Li 1, Edward M Mills 2, Joseph L Borowitz 1, Gary E. Isom 1*

1 Purdue University 2 Division of Pharmacology and Toxicology, School of Pharmacy, University of Texas at Austin

* Address correspondence to: E-mail: geisom{at}purdue.edu

Abstract

Uncoupling protein 2 (UCP-2) regulates mitochondrial function by increasing proton leak across the inner membrane to dissociate respiration from ATP synthesis and reduce reactive oxygen species (ROS) generation. A number of studies have shown that UCP-2 expression protect cells from oxidative stress mediated injuries. In the current study we show UCP-2 mediated reduction in mitochondrial function contributes to the mitochondrial dysfunction and the necrotic death of primary cultured mesencephalic cells (MC) after exposure to cyanide, a complex IV inhibitor. The necrotic cell death was directly related to the level of mitochondrial dysfunction, as shown by reduction in ATP levels and decreased mitochondrial membrane potential ({Delta}{psi} m ). Treatment with cyanide for 6 h or longer upregulated UCP-2 expression. Blockade of upregulation with a transcription or a translational inhibitor reduced the response to cyanide. Knockdown with RNAi or transfection with a UCP-2 dominant negative interfering mutant reduced the cyanide-induced mitochondrial dysfunction and cell death, showing that constitutive expression of UCP-2 plays a role in the response to cyanide. Overexpression of UCP-2 by transfection with human full length cDNA potentiated the cyanide toxicity. These findings indicate that UCP-2 can serve as a regulator of mitochondria-mediated necrotic cell death in which enhanced expression can increase the vulnerability of primary MC cells to injury due to complex IV-mediated inhibition by cyanide.


Key words: ATP, cyanide, mitochondria, necrosis, reactive oxygen species, uncoupling protein-2


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