A suggested role for mitochondria in Noonan syndrome

Biochim Biophys Acta. 2010 Feb;1802(2):275-83. doi: 10.1016/j.bbadis.2009.10.005. Epub 2009 Oct 14.


Noonan syndrome (NS) is an autosomal dominant disorder, and a main feature is congenital heart malformation. About 50% of cases are caused by gain-of-function mutations in the tyrosine phosphatase SHP2/PTPN11, a downstream regulator of ERK/MAPK. Recently it was reported that SHP2 also localizes to the mitochondrial intercristae/intermembrane space (IMS), but the role of SHP2 in mitochondria is unclear. The mitochondrial oxidative phosphorylation (OxPhos) system provides the vast majority of cellular energy and produces reactive oxygen species (ROS). Changes in ROS may interfere with organ development such as that observed in NS patients. Several phosphorylation sites have been found in OxPhos components including cytochrome c oxidase (CcO) and cytochrome c (Cytc), and we hypothesized that OxPhos complexes may be direct or indirect targets of SHP2. We analyzed mitochondrial function using mouse fibroblasts from wild-types, SHP2 knockdowns, and D61G SHP2 mutants leading to constitutively active SHP2, as found in NS patients. Levels of OxPhos complexes were similar except for CcO and Cytc, which were 37% and 28% reduced in the D61G cells. However, CcO activity was significantly increased, as we also found for two lymphoblast cell lines from NS patients with two independent mutations in PTPN11. D61G cells showed lower mitochondrial membrane potential and 30% lower ATP content compared to controls. ROS were significantly increased; aconitase activity, a marker for ROS-induced damage, was decreased; and catalase activity was increased in D61G cells. We propose that decreased energy levels and/or increased ROS may explain, at least in part, some of the clinical features in NS that overlap with children with mitochondrial disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cytochromes c / genetics
  • Cytochromes c / metabolism
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Fibroblasts / physiology
  • Humans
  • Kinetics
  • Membrane Potentials
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mitochondria / enzymology*
  • Mitochondria / physiology
  • Mitochondrial Membranes / physiology
  • Mutation
  • Noonan Syndrome / enzymology
  • Noonan Syndrome / genetics*
  • Oxidative Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Reactive Oxygen Species / metabolism
  • Reference Values


  • Reactive Oxygen Species
  • Cytochromes c
  • Electron Transport Complex IV
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11