DARD, Laetitia; HUBERT, Christophe; ESTEVES, Pauline; BLANCHARD, Wendy; BOU ABOUT, Ghina; BALDASSERONI, Lyla; DUMON, Elodie; ANGELINI, Chloe; DELOURME, Megane; GUYONNET-DUPERAT, Veronique; CLAVEROL, Stephane; FONTENILLE, Laura; KISSA, Karima; SEGUELA, Pierre-Emmanuel; THAMBO, Jean-Benoit; NICOLAS, Levy; HERAULT, Yann; BELLANCE, Nadege; DIAS AMOEDO, Nivea; MAGDINIER, Frederique; SORG, Tania; LACOMBE, Didier; ROSSIGNOL, Rodrigue

doi:10.1172/JCI131053

Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

HUBERT, Christophe
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

ESTEVES, Pauline
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

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Article de revue

Ce document a été publié dans

The Journal of clinical investigation. 2022-04-15, vol. 132, n° 8

Résumé en anglais

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 CS 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 CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.< Réduire

Mots clés en anglais

AMP-Activated Protein Kinases

Animals

Costello Syndrome

Germ-Line Mutation

Homeostasis

Humans

Mice

Proto-Oncogene Proteins p21(ras)

Zebrafish

URI

https://oskar-bordeaux.fr/handle/20.500.12278/183313

DOI

http://dx.doi.org/10.1172/JCI131053

Unités de recherche

Maladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211

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

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Résumé en anglais

Mots clés en anglais

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DOI

Unités de recherche