PMID- 19835954
OWN - NLM
STAT- MEDLINE
DCOM- 20100401
LR  - 20211020
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1802
IP  - 2
DP  - 2010 Feb
TI  - A suggested role for mitochondria in Noonan syndrome.
PG  - 275-83
LID - 10.1016/j.bbadis.2009.10.005 [doi]
AB  - 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.
CI  - Copyright 2009 Elsevier B.V. All rights reserved.
FAU - Lee, Icksoo
AU  - Lee I
AD  - Center for Molecular Medicine and Genetics, Wayne State University School of 
      Medicine, 3214 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA.
FAU - Pecinova, Alena
AU  - Pecinova A
FAU - Pecina, Petr
AU  - Pecina P
FAU - Neel, Benjamin G
AU  - Neel BG
FAU - Araki, Toshiyuki
AU  - Araki T
FAU - Kucherlapati, Raju
AU  - Kucherlapati R
FAU - Roberts, Amy E
AU  - Roberts AE
FAU - Huttemann, Maik
AU  - Huttemann M
LA  - eng
GR  - R37 CA49132/CA/NCI NIH HHS/United States
GR  - R01 HL083273/HL/NHLBI NIH HHS/United States
GR  - R37 CA049152-23/CA/NCI NIH HHS/United States
GR  - R01 HL083273-04/HL/NHLBI NIH HHS/United States
GR  - R37 CA049152/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091014
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Reactive Oxygen Species)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - EC 3.1.3.48 (PTPN11 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/cytology/metabolism/pathology
MH  - Cytochromes c/genetics/metabolism
MH  - Electron Transport Complex IV/genetics/metabolism
MH  - Fibroblasts/enzymology/metabolism/physiology
MH  - Humans
MH  - Kinetics
MH  - Membrane Potentials
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Mutant Strains
MH  - Mitochondria/*enzymology/physiology
MH  - Mitochondrial Membranes/physiology
MH  - Mutation
MH  - Noonan Syndrome/enzymology/*genetics
MH  - Oxidative Phosphorylation
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/deficiency/*genetics
MH  - Reactive Oxygen Species/metabolism
MH  - Reference Values
PMC - PMC2878584
MID - NIHMS204408
EDAT- 2009/10/20 06:00
MHDA- 2010/04/02 06:00
PMCR- 2010/05/29
CRDT- 2009/10/20 06:00
PHST- 2009/07/23 00:00 [received]
PHST- 2009/09/30 00:00 [revised]
PHST- 2009/10/07 00:00 [accepted]
PHST- 2009/10/20 06:00 [entrez]
PHST- 2009/10/20 06:00 [pubmed]
PHST- 2010/04/02 06:00 [medline]
PHST- 2010/05/29 00:00 [pmc-release]
AID - S0925-4439(09)00239-7 [pii]
AID - 10.1016/j.bbadis.2009.10.005 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2010 Feb;1802(2):275-83. doi: 10.1016/j.bbadis.2009.10.005. 
      Epub 2009 Oct 14.