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CRIF1 deficiency induces p66shc-mediated oxidative stress and endothelial activation

Harsha Nagar1, Saet-byel Jung2, Sun Kwan Kwon1

  • 1Department of physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea.

Plos One
|June 7, 2014
PubMed

Insights

Mitochondrial dysfunction from CRIF1 knockdown increases oxidative stress by activating p66shc, contributing to endothelial cell activation. Targeting p66shc may mitigate this cardiovascular disease pathway.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Medicine
  • Cellular Stress Response

Background:

  • Mitochondrial dysfunction is central to cardiovascular diseases.
  • CRISPR-associated factor 1 (CRIF1) knockdown impairs mitochondrial function and elevates reactive oxygen species (ROS).
  • p66shc, a redox enzyme, mediates oxidative stress in endothelial cells.

Purpose of the Study:

  • To investigate if CRIF1 knockdown-induced mitochondrial dysfunction stimulates p66shc.
  • To determine p66shc's role in endothelial activation under mitochondrial stress.

Main Methods:

  • CRISPR-associated factor 1 (CRIF1) knockdown in endothelial cells.
  • Assessed mitochondrial oxidative phosphorylation (OXPHOS) complexes, mitochondrial ROS (mtROS), and membrane potential.
  • Measured p66shc phosphorylation, cytosolic ROS, and endothelial activation markers (VCAM-1, ER stress).
  • Utilized p66shc knockdown to evaluate its functional impact.

Main Results:

  • CRISPR-associated factor 1 (CRIF1) knockdown reduced OXPHOS, increased mtROS, and altered mitochondrial membrane potential.
  • CRISPR-associated factor 1 (CRIF1) knockdown enhanced p66shc phosphorylation and cytosolic ROS production.
  • CRISPR-associated factor 1 (CRIF1) knockdown upregulated VCAM-1 and ER stress markers.
  • p66shc knockdown attenuated mitochondrial dysfunction, ROS production, and endothelial activation.

Conclusions:

  • CRISPR-associated factor 1 (CRIF1) knockdown-induced mitochondrial dysfunction activates p66shc.
  • p66shc plays a significant role in mediating endothelial activation secondary to mitochondrial dysfunction.
  • These findings highlight a novel pathway linking mitochondrial health and endothelial function in cardiovascular disease.

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