ToxSci Advance Access originally published online on March 30, 2005
Toxicological Sciences 2005 86(1):116-124; doi:10.1093/toxsci/kfi164
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Enhancement of Cyanide-Induced Mitochondrial Dysfunction and Cortical Cell Necrosis by Uncoupling Protein-2
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* Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907–1333; Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892
Received February 1, 2005; accepted March 28, 2005
Uncoupling protein 2 (UCP-2) is expressed in the inner mitochondrial membrane and modulates mitochondrial function by partially uncoupling oxidative phosphorylation, and it 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 potassium cyanide (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.
Key Words: apoptosis; cyanide; necrosis; mitochondria; uncoupling protein.
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