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ToxSci Advance Access published online on March 30, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi164
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received February 1, 2005
Accepted March 28, 2005

Neurotoxicology

Enhancement of Cyanide-Induced Mitochondrial Dysfunction and Cortical Cell Necrosis by Uncoupling Protein-2

L. Li 1, K. Prabhakaran 1, E.M. Mills 2, J.L. Borowitz 1, and G.E. Isom 1*

1 Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333
2 Cardiovascular Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

* To whom correspondence should be addressed.
G.E. Isom, E-mail: geisom{at}purdue.edu


  Abstract

Uncoupling protein 2 (UCP-2) is expressed in the inner mitochondrial membrane and modulates mitochondrial function by partially uncoupling oxidative phosphorylation and has been reported to modulate cell death. Cyanide is a potent neurotoxin that inhibits complex IV to alter mitochondrial function to induce neuronal death. In primary rat cortical cells KCN produced an apoptotic death at 200-400 µM. Higher concentrations of KCN (500-600 µM) switched the mode of death from apoptosis to necrosis. In necrotic cells, ATP levels were severely depleted as compared to cortical cells undergoing apoptosis. To determine if UCP-2 expression could alter KCN-induced cell death, cells were transiently transfected with full-length human UCP-2 cDNA (UCP-2+). Overexpression switched the mode of death produced by KCN (400 µM) from apoptosis to necrosis. The change in cell death was mediated by impaired mitochondrial function as reflected by a marked decrease of ATP levels and reduction in mitochondrial membrane potential. RNA interference or transfection with a dominant interfering mutant blocked the necrotic response observed in UCP-2+ cells. Additionally, treatment of UCP-2+ cells with cyclosporin A blocked necrosis, indicating the involvement of mitochondrial permeability pore transition in the necrotic death. These results show that increased expression of UCP-2 alters the response to a potent mitochondrial toxin by switching the mode of cell death from apoptosis to necrosis. It is concluded that UCP-2 levels influence cellular responses to cyanide-induced mitochondrial dysfunction.

Keywords: apoptosis; cyanide; necrosis; mitochondria; uncoupling protein.
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