Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species.

Germline activating mutations in HRAS cause Costello Syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via ROS-dependent AMPKα and p38 hyperactivation, occurs in CS, resulting in accelerated glycolysis, and increased fatty acid synthesis and storage as lipid droplets in primary fibroblasts. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. Concomitant inhibition of p38 and PI3K signaling by wortmannin was able to rescue both the dysregulated glucose intake and accelerated autophagic flux. Our findings provide a mechanistic link between upregulated HRAS function, defective growth and increased resting energetic expenditure in CS, and document that targeting p38 and PI3K signaling is able to revert this metabolic dysfunction.