TY - JOUR
T1 - Mechanical stretch exacerbates the cell death in SH-SY5Y cells exposed to paraquat
T2 - Mitochondrial dysfunction and oxidative stress
AU - Wang, Fang
AU - Franco, Rodrigo
AU - Skotak, Maciej
AU - Hu, Gang
AU - Chandra, Namas
N1 - Funding Information:
This work was supported by the US Army Research Office project “Army-UNL Center of Trauma Mechanics” (Contract No.W911NF08-10483) and the National Institutes of Health Grant P20RR17675 , Centers of Biomedical Research Excellence (COBRE) . We are grateful to Dr. Charles A. Kuszynski, and Zhi Hong Gill at the Nebraska Center for Virology for their help with flow cytometry analyses.
PY - 2014/3
Y1 - 2014/3
N2 - Recent studies suggest that traumatic brain injury (TBI) and pesticide exposure increase the risk of Parkinson's disease (PD), but the molecular mechanisms involved remain unclear. Using an in vitro model of TBI, we evaluated the role of mitochondrial membrane potential (δΨm) and mitochondrial reactive oxygen species (ROS) induced by stretch on dopaminergic cell death upon paraquat exposure. Human dopaminergic neuroblastoma SH-SY5Y cells grown on silicone membrane were stretched at mild (25%) and moderate (50%) strain prior to paraquat exposure. We observed that moderate stretch (50% strain) increased the vulnerability of cells to paraquat demonstrated by the loss of plasma membrane integrity (propidium iodide-uptake) and decreased mitochondrial activity (MTT assay). Mitochondrial depolarization occurred immediately after stretch, while mitochondrial ROS increased rapidly and remained elevated for up to 4. h after the stretch injury. Intracellular glutathione (GSH) stores were also transiently decreased immediately after moderate stretch. Cells treated with paraquat, or moderate stretch exhibited negligible mitochondrial depolarization at 48. h post treatment, whereas in cells stretched prior to paraquat exposure, a significant mitochondrial depolarization occurred compared to samples exposed to either paraquat or stretch. Moderate stretch also increased mitochondrial ROS formation, as well as exacerbated intracellular GSH loss induced by paraquat. Overexpression of manganese superoxide dismutase (MnSOD) markedly diminished the deleterious effects of stretch in paraquat neurotoxicity. Our findings demonstrate that oxidative stress induced by mitochondrial dysfunction plays a critical role in the synergistic toxic effects of stretch (TBI) and pesticide exposure. Mitigation of oxidative stress via mitochondria-targeted antioxidants appears an attractive route for treatment of neurodegeneration mediated by TBI.
AB - Recent studies suggest that traumatic brain injury (TBI) and pesticide exposure increase the risk of Parkinson's disease (PD), but the molecular mechanisms involved remain unclear. Using an in vitro model of TBI, we evaluated the role of mitochondrial membrane potential (δΨm) and mitochondrial reactive oxygen species (ROS) induced by stretch on dopaminergic cell death upon paraquat exposure. Human dopaminergic neuroblastoma SH-SY5Y cells grown on silicone membrane were stretched at mild (25%) and moderate (50%) strain prior to paraquat exposure. We observed that moderate stretch (50% strain) increased the vulnerability of cells to paraquat demonstrated by the loss of plasma membrane integrity (propidium iodide-uptake) and decreased mitochondrial activity (MTT assay). Mitochondrial depolarization occurred immediately after stretch, while mitochondrial ROS increased rapidly and remained elevated for up to 4. h after the stretch injury. Intracellular glutathione (GSH) stores were also transiently decreased immediately after moderate stretch. Cells treated with paraquat, or moderate stretch exhibited negligible mitochondrial depolarization at 48. h post treatment, whereas in cells stretched prior to paraquat exposure, a significant mitochondrial depolarization occurred compared to samples exposed to either paraquat or stretch. Moderate stretch also increased mitochondrial ROS formation, as well as exacerbated intracellular GSH loss induced by paraquat. Overexpression of manganese superoxide dismutase (MnSOD) markedly diminished the deleterious effects of stretch in paraquat neurotoxicity. Our findings demonstrate that oxidative stress induced by mitochondrial dysfunction plays a critical role in the synergistic toxic effects of stretch (TBI) and pesticide exposure. Mitigation of oxidative stress via mitochondria-targeted antioxidants appears an attractive route for treatment of neurodegeneration mediated by TBI.
KW - Mitochondria
KW - MnSOD
KW - Paraquat
KW - Reactive oxygen species
KW - Traumatic brain injury
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U2 - 10.1016/j.neuro.2014.01.002
DO - 10.1016/j.neuro.2014.01.002
M3 - Article
C2 - 24462953
AN - SCOPUS:84893496019
SN - 0161-813X
VL - 41
SP - 54
EP - 63
JO - NeuroToxicology
JF - NeuroToxicology
ER -