Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity

Tumor necrosis factor alpha (TNF-alpha) is known to exacerbate ischemic brain injury; however, the mechanism is unknown. Previous studies have evaluated the effects of TNF-alpha on neurons with long exposures to high doses of TNF-alpha, which is not pathophysiologically relevant. We characterized the rapid effects of TNF-alpha on basal respiration, ATP production, and maximal respiration using pathophysiologically relevant, poststroke concentrations of TNF-alpha. We observed a reduction in mitochondrial function as early as 1.5 h after exposure to low doses of TNF-alpha, followed by a decrease in cell viability in HT-22 cells and primary neurons. Subsequently, we used the HT-22 cell line to determine the mechanism by which TNF-alpha causes a rapid and profound reduction in mitochondrial function. Pre-treating with TNF-R1 antibody, but not TNF-R2 antibody, ameliorated the neurotoxic effects of TNF-alpha, indicating that TNF-alpha exerts its neurotoxic effects through TNF-R1. We observed an increase in caspase 8 activity and a decrease in mitochondrial membrane potential after exposure to TNF-alpha which resulted in a release of cytochrome c from the mitochondria into the cytosol. These novel findings indicate for the first time that an acute exposure to pathophysiologically relevant concentrations of TNF-alpha has neurotoxic effects mediated by a rapid impairment of mitochondrial function.