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Rapid mitochondrial dysfunction mediates TNF-α induced neurotoxicity

Significance Statement

TNF-α is a pro-inflammatory cytokine that is increased during stroke and has been associated with worse clinical outcome in patients.  Although TNF-α has been shown to be associated with poor health outcomes after stroke, it is not well understood how.  Thus, we determined one mechanism by which TNF-α could be negatively affecting stroke outcome. Neurons have a high ATP demand, and a temporary reduction in mitochondrial function can result in a profound decrease in neuronal viability.  We discovered that at clinically relevant concentrations of TNF-α that is found in the serum of stroke patients, neuronal mitochondrial function is rapidly and profoundly decreased.  These neurons go on to die after their mitochondria are affected.  Thus during stroke, the increase in TNF-α in the brain can result in more brain tissue damage after stroke leading to poor health outcomes.  Stroke is the 4th leading cause of death in the United States and currently only has one FDA approved treatment.  Thus, we are in critical need for more clinical interventions for stroke and our research indicates that reducing TNF-α and/or increasing mitochondrial function may be a possible therapeutic target for stroke.

Journal Reference

Doll DN, Rellick SL, Barr TL, Ren X, Simpkins JW. J Neurochem. 2015 ;132(4):443-51.

Neurobiology and Anatomy, West Virginia University, Morgantown, West Virginia, USA; Center for Neuroscience, Morgantown, WV, USA; Center for Basic and Translational Stroke Research, Morgantown, WV, USA.

Abstract

Tumor necrosis factor alpha (TNF-α) is known to exacerbate ischemic brain injury; however, the mechanism is unknown. Previous studies have evaluated the effects of TNF-α on neurons with long exposures to high doses of TNF-α, which is not pathophysiologically relevant. We characterized the rapid effects of TNF-α on basal respiration, ATP production, and maximal respiration using pathophysiologically relevant, post-stroke concentrations of TNF-α. We observed a reduction in mitochondrial function as early as 1.5 h after exposure to low doses of TNF-α, 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-α 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-α, indicating that TNF-α 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-α 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-α has neurotoxic effects mediated by a rapid impairment of mitochondrial function. This study focuses on the neurotoxic mechanism of a pro-inflammatory  cytokine, tumor necrosis factor alpha (TNF-α). We demonstrate a prompt mitochondrial dysfunction followed by nerve cell loss after exposure to TNF-α. These studies may provide evidence that the immune system can rapidly and adversely affect brain function and that TNF-α signaling may be a target for neuroprotection.

© 2014 International Society for Neurochemistry.

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