A suggested role for mitochondria in Noonan syndrome

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1802

Article

Lee, Icksoo¹  Pecinova, Alena¹  Pecina, Petr¹  Neel, Benjamin G.²  Araki, Toshiyuki²  Kucherlapati, Raju³  Roberts, Amy E.⁴  Huettemann, Maik¹ 

[1] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA

[2] Ontario Canc Inst, Toronto, ON M4X 1K9, Canada

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Childrens Hosp, Boston, MA 02115 USA

关键词: Cardio-facio-cutaneous syndrome;    Cytochrome c oxidase;    Noonan syndrome;    Mitochondria;    Oxidative phosphorylation;    PTPN11;    Reactive oxygen species;    SHP2;   

DOI  :  10.1016/j.bbadis.2009.10.005

来源: Elsevier

【 摘 要 】

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 INS 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. (C) 2009 Elsevier B.V. All rights reserved.

【 授权许可】

Free