Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells

Neurosignals. 2012;20(4):265-80. doi: 10.1159/000333069. Epub 2012 Feb 23.


Endoplasmic reticulum (ER) and mitochondrial stress are considered causal factors that induce neurodegenerative diseases. However, the relationship between these stresses remains poorly understood. To investigate the molecular mechanism underlying crosstalk between the ER and mitochondria in neurodegeneration, we treated SH-SY5Y human neuroblastoma cells with thapsigargin and tunicamycin, two inducers of ER stress, and atrazine, a promoter of mitochondrial stress. Each pharmacological agent caused mitochondrial dysfunction, which was characterized by reduced intracellular ATP, mitochondrial membrane potential, and endogenous cellular respiration as well as an augmentation of oxidative stress. Oligonucleotide microarray analysis followed by semiquantitative RT-PCR validation assays revealed that thapsigargin and tunicamycin downregulated the expression of most mitochondria-related genes in a manner similar to that induced by atrazine. In contrast, atrazine did not alter the expression of markers of ER stress. Three-dimensional principal component analysis showed that the gene expression profile produced by atrazine treatment was distinct from that generated by ER stress. However, all three agents impaired insulin receptor substrate-1 and Akt phosphorylation in the insulin signaling pathway. Ectopic overexpression of mitochondrial transcription factor A reversed the effects of thapsigargin on mitochondria and Akt signaling. We conclude that ER stress induces neuronal cell death through common perturbation of mitochondrial function and Akt signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Apoptosis / drug effects
  • Atrazine / toxicity
  • Blotting, Western
  • Cell Line
  • Coloring Agents
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology*
  • Fluoresceins
  • Herbicides / toxicity
  • Humans
  • Insulin / physiology*
  • Microarray Analysis
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Mitochondrial Membranes / drug effects
  • Neurons / physiology
  • Oxygen Consumption / drug effects
  • Real-Time Polymerase Chain Reaction
  • Receptor Cross-Talk / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tetrazolium Salts
  • Thiazoles
  • Transfection


  • Coloring Agents
  • Fluoresceins
  • Herbicides
  • Insulin
  • Tetrazolium Salts
  • Thiazoles
  • Adenosine Triphosphate
  • thiazolyl blue
  • Atrazine
  • fluorexon