HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

Area of Science:

• Molecular Biology
• Genetics
• Developmental Biology
• Cardiology

Background:

• RASopathies are rare developmental disorders caused by germline mutations in the RAS/MAPK signaling pathway.
• Costello syndrome (CS) is a RASopathy characterized by various developmental abnormalities.

Purpose of the Study:

• To investigate the molecular mechanisms underlying Costello syndrome.
• To explore the role of mitochondrial dysfunction in CS pathophysiology.
• To evaluate potential therapeutic strategies targeting mitochondrial pathways.

Main Methods:

• Utilized a mouse model with HRAS p.G12S mutation, patient-derived fibroblasts, and hiPSC-cardiomyocytes.
• Employed a zebrafish model with HRAS p.G12V mutation and lentiviral constructs for HRAS mutations.
• Analyzed mitochondrial proteostasis, oxidative phosphorylation, and AMPK signaling.

Main Results:

• Identified altered mitochondrial proteostasis and defective oxidative phosphorylation in CS models (heart, skeletal muscle, cells).
• Demonstrated that mutant HRAS inhibits the AMPK signaling pathway, impacting mitochondrial function.
• Showed that pharmacological activation of mitochondrial bioenergetics and quality control ameliorated CS phenotypes in vitro and in vivo.

Conclusions:

• Mitochondrial proteostasis and bioenergetics are crucial in RASopathy pathophysiology.
• Inhibition of AMPK signaling by mutant HRAS contributes to mitochondrial defects in CS.
• Mitochondrial modulators represent a promising therapeutic avenue for Costello syndrome patients.