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Rapid mitochondrial dysfunction mediates TNF ‐alpha‐induced neurotoxicity
Author(s) -
Doll Danielle N.,
Rellick Stephanie L.,
Barr Taura L.,
Ren Xuefang,
Simpkins James W.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13008
Subject(s) - neurotoxicity , alpha (finance) , mitochondrion , chemistry , biology , neuroscience , microbiology and biotechnology , biochemistry , medicine , toxicity , construct validity , nursing , organic chemistry , patient satisfaction
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.