HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models.
| dc.rights.license | open | en_US |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | DARD, Laetitia | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | HUBERT, Christophe | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | ESTEVES, Pauline | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | BLANCHARD, Wendy | |
| dc.contributor.author | BOU ABOUT, Ghina | |
| dc.contributor.author | BALDASSERONI, Lyla | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | DUMON, Elodie | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | ANGELINI, Chloe | |
| dc.contributor.author | DELOURME, Megane | |
| dc.contributor.author | GUYONNET-DUPERAT, Veronique | |
| dc.contributor.author | CLAVEROL, Stephane | |
| hal.structure.identifier | AZELEAD | |
| dc.contributor.author | FONTENILLE, Laura | |
| dc.contributor.author | KISSA, Karima | |
| dc.contributor.author | SEGUELA, Pierre-Emmanuel | |
| hal.structure.identifier | Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] [CRCTB] | |
| dc.contributor.author | THAMBO, Jean-Benoit | |
| dc.contributor.author | NICOLAS, Levy | |
| dc.contributor.author | HERAULT, Yann | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | BELLANCE, Nadege | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | DIAS AMOEDO, Nivea | |
| dc.contributor.author | MAGDINIER, Frederique | |
| dc.contributor.author | SORG, Tania | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | LACOMBE, Didier | |
| hal.structure.identifier | Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM] | |
| dc.contributor.author | ROSSIGNOL, Rodrigue | |
| dc.date.accessioned | 2023-07-05T14:48:43Z | |
| dc.date.available | 2023-07-05T14:48:43Z | |
| dc.date.issued | 2022-04-15 | |
| dc.identifier.issn | 1558-8238 | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/183313 | |
| dc.description.abstractEn | 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. | |
| dc.language.iso | EN | en_US |
| dc.rights | Attribution 3.0 United States | * |
| dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
| dc.subject.en | AMP-Activated Protein Kinases | |
| dc.subject.en | Animals | |
| dc.subject.en | Costello Syndrome | |
| dc.subject.en | Germ-Line Mutation | |
| dc.subject.en | Homeostasis | |
| dc.subject.en | Humans | |
| dc.subject.en | Mice | |
| dc.subject.en | Proto-Oncogene Proteins p21(ras) | |
| dc.subject.en | Zebrafish | |
| dc.title.en | HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models. | |
| dc.title.alternative | J Clin Invest | en_US |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1172/JCI131053 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Génétique | en_US |
| dc.identifier.pubmed | 35230976 | en_US |
| bordeaux.journal | The Journal of clinical investigation | en_US |
| bordeaux.volume | 132 | en_US |
| bordeaux.hal.laboratories | Maladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211 | en_US |
| bordeaux.issue | 8 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.institution | INSERM | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.import.source | pubmed | |
| hal.popular | non | en_US |
| hal.audience | Internationale | en_US |
| hal.export | false | |
| workflow.import.source | pubmed | |
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