Fiche publication
Date publication
mars 2022
Journal
The Journal of clinical investigation
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann
,
Dr SORG Tania
Tous les auteurs :
Dard L, Hubert C, Esteves P, Blanchard W, Bou About G, Baldasseroni L, Dumon E, Angelini C, Delourme M, Guyonnet-Duperat V, Claverol S, Bonneu M, Fontenille L, Kissa K, Séguéla PE, Thambo JB, Levy N, Herault Y, Bellance N, Dias Amoedo N, Magdinier F, Sorg T, Lacombe D, Rossignol R
Lien Pubmed
Résumé
Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of Costello mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in the CS mice and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis in the pathophysiology of RASopathies and suggest that patients with Costello syndrome may benefit from treatment with mitochondrial modulators.
Mots clés
Bioenergetics, Metabolism
Référence
J Clin Invest. 2022 Mar 1;:
