Oxidative stress-dependent p66Shc phosphorylation in skin fibroblasts of children with mitochondrial disorders

Biochim Biophys Acta. Jun-Jul 2010;1797(6-7):952-60. doi: 10.1016/j.bbabio.2010.03.005. Epub 2010 Mar 10.

Abstract

p66Shc, the growth factor adaptor protein, can have a substantial impact on mitochondrial metabolism through regulation of cellular response to oxidative stress. We investigated relationships between the extent of p66Shc phosphorylation at Ser36, mitochondrial dysfunctions and an antioxidant defense reactions in fibroblasts derived from five patients with various mitochondrial disorders (two with mitochondrial DNA mutations and three with methylglutaconic aciduria and genetic defects localized, most probably, in nuclear genes). We found that in all these fibroblasts, the extent of p66Shc phosphorylation at Ser36 was significantly increased. This correlated with a substantially decreased level of mitochondrial superoxide dismutase (SOD2) in these cells. This suggest that SOD2 is under control of the Ser36 phosphorylation status of p66Shc protein. As a consequence, an intracellular oxidative stress and accumulation of damages caused by oxygen free radicals are observed in the cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / genetics
  • Amino Acid Metabolism, Inborn Errors / metabolism
  • Case-Control Studies
  • Cells, Cultured
  • DNA, Mitochondrial / genetics
  • Female
  • Fibroblasts / metabolism
  • Glutarates / urine
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Models, Biological
  • Mutation
  • Oxidative Stress
  • Phosphorylation
  • Serine / chemistry
  • Shc Signaling Adaptor Proteins / chemistry
  • Shc Signaling Adaptor Proteins / metabolism*
  • Skin / metabolism
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1

Substances

  • DNA, Mitochondrial
  • Glutarates
  • SHC1 protein, human
  • SOD1 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Serine
  • 3-methylglutaconic acid
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • superoxide dismutase 2