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TOXICOLOGY

Up-Regulation of Uncoupling Protein 2 by Cyanide Is Linked with Cytotoxicity in Mesencephalic Cells

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (K.P., L.L., J.L.B., G.E.I.); and Division of Pharmacology and Toxicology, School of Pharmacy, University of Texas, Austin, Texas (E.M.M.)

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 generation. A number of studies have shown that UCP-2 expression protects 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 (MCs) 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. Treatment with cyanide for 6 h or longer upregulated UCP-2 expression. Blockade of up-regulation 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 MCs to injury due to complex IV-mediated inhibition by cyanide.

Address correspondence to: Dr. Gary E. Isom, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333. E-mail: geisom{at}purdue.edu

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