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Prooxidant properties of p66shc are mediated by mitochondria in human cells

Evgeny R Galimov1, Boris V Chernyak2, Alena S Sidorenko3

  • 1Belozersky Institute of Physical and Chemical Biology, Moscow State University, Moscow, Russia; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Plos One
|March 13, 2014
PubMed

Insights

The protein p66Shc drives mitochondrial reactive oxygen species (ROS) production during oxidative stress in human cells. Reducing p66Shc levels mitigates ROS and protects mitochondria, highlighting its role in cellular aging and cancer.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • p66Shc, a product of the SHC1 gene, exhibits pro-oxidant and pro-apoptotic functions linked to aging.
  • Mitochondria are implicated in p66Shc-mediated reactive oxygen species (ROS) production, but mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of p66Shc in oxidative stress-induced ROS production.
  • To determine the mitochondrial contribution to p66Shc-dependent ROS generation in human cells.

Main Methods:

  • Utilized human colon carcinoma RKO cells and diploid human dermal fibroblasts (HDFs).
  • Employed shRNA-mediated knockdown and recombinant p66Shc overexpression.
  • Assessed ROS production using HyPer-mito sensor and observed mitochondrial fragmentation.
  • Studied mitochondrial DNA-depleted ρ0-RKO cells and mitochondria-targeted antioxidants (SkQ1, SkQR1).

Main Results:

  • p66Shc knockdown suppressed ROS production, while overexpression stimulated it in RKO and HDF cells.
  • The effect of p66Shc on ROS was absent in ρ0-RKO cells lacking the mitochondrial electron transport chain.
  • p66Shc-dependent mitochondrial ROS accumulation and subsequent mitochondrial fragmentation were observed.
  • Mitochondria-targeted antioxidants reduced oxidative stress.

Conclusions:

  • p66Shc-dependent ROS production during oxidative stress originates from mitochondria in human normal and cancer cells.
  • p66Shc plays a critical role in mediating mitochondrial oxidative stress.
  • Targeting mitochondrial ROS could be a therapeutic strategy for p66Shc-related conditions.

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