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NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis

Gang Li1, Christopher Scull, Lale Ozcan

  • 1Department of Medicine, Columbia University, New York, NY 10032, USA.

The Journal of Cell Biology
|December 8, 2010
PubMed

Insights

Endoplasmic reticulum (ER) stress induces apoptosis via nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX)-mediated oxidative stress. Blocking NOX2 or using antioxidants prevents this, revealing a key pathway in chronic diseases.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Pathophysiology

Background:

  • Endoplasmic reticulum (ER) stress and oxidative stress are implicated in chronic diseases.
  • The interplay between ER stress, oxidative stress, and apoptosis in vivo is not well understood.

Purpose of the Study:

  • To investigate the molecular mechanisms linking ER stress, oxidative stress, and apoptosis.
  • To explore the role of nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) in ER-induced apoptosis.

Main Methods:

  • Utilized a previously identified ER stress-apoptosis pathway.
  • Investigated the effects of genetic deletion of NOX2 and antioxidant treatment (N-acetylcysteine).
  • Examined CCAAT/enhancer binding protein homologous protein (CHOP) induction and apoptosis in vivo.

Main Results:

  • ER stress pathway induces NOX and NOX-mediated oxidative stress, leading to apoptosis.
  • Genetic deletion of NOX2 and N-acetylcysteine treatment blocked apoptosis.
  • NOX and oxidative stress amplify CHOP induction via double-stranded RNA-dependent protein kinase (PKR) activation.
  • NOX2 deficiency protected mice from ER-induced renal cell apoptosis and dysfunction.

Conclusions:

  • ER stress, NOX-mediated oxidative stress, and PKR activation are integrated pathways inducing apoptosis.
  • NOX2 plays a critical role in ER stress-induced apoptosis and renal dysfunction.
  • Targeting this pathway may offer therapeutic strategies for chronic diseases involving ER stress.

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