Disrupted ATP synthase activity and mitochondrial hyperpolarisation-dependent oxidative stress is associated with p66Shc phosphorylation in fibroblasts of NARP patients

Int J Biochem Cell Biol. 2013 Jan;45(1):141-50. doi: 10.1016/j.biocel.2012.07.020. Epub 2012 Jul 31.


p66Shc is an adaptor protein involved in cell proliferation and differentiation that undergoes phosphorylation at Ser36 in response to oxidative stimuli, consequently inducing a burst of reactive oxygen species (ROS), mitochondrial disruption and apoptosis. Its role during several pathologies suggests that p66Shc mitochondrial signalling can perpetuate a primary mitochondrial defect, thus contributing to the pathophysiology of that condition. Here, we show that in the fibroblasts of neuropathy, ataxia and retinitis pigmentosa (NARP) patients, the p66Shc phosphorylation pathway is significantly induced in response to intracellular oxidative stress related to disrupted ATP synthase activity and mitochondrial membrane hyperpolarisation. We postulate that the increased phosphorylation of p66Shc at Ser36 is partially responsible for further increasing ROS production, resulting in oxidative damage of proteins. Oxidative stress and p66Shc phosphorylation at Ser36 may be mitigated by antioxidant administration or the use of a p66Shc phosphorylation inhibitor. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Fibroblasts / metabolism*
  • Humans
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Myopathies / genetics
  • Mitochondrial Myopathies / metabolism*
  • Mitochondrial Myopathies / pathology
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Oxidative Phosphorylation
  • Oxidative Stress / physiology*
  • Phosphorylation
  • Reactive Oxygen Species / metabolism
  • Retinitis Pigmentosa / genetics
  • Retinitis Pigmentosa / metabolism*
  • Retinitis Pigmentosa / pathology
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism*
  • Signal Transduction
  • Src Homology 2 Domain-Containing, Transforming Protein 1


  • Reactive Oxygen Species
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Mitochondrial Proton-Translocating ATPases

Supplementary concepts

  • Neuropathy ataxia and retinitis pigmentosa