ArticleThe Journal of clinical investigation2022
HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 28 citations in OpenAlex.
- Article
- Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort.Frontiers in immunology · 2025Observational
- Non-Mammalian Models for Understanding Neurological Defects in RASopathies.Biomedicines · 2024Review
- The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.American journal of medical genetics. Part A · 2024Article
- Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.JCI insight · 2024Article
- In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease.International journal of molecular sciences · 2024Review
- Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues.Communications biology · 2023Article
- Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.Frontiers in endocrinology · 2023Review
- Lipid profile in Noonan syndrome and related disorders: trend by age, sex and genotype.Frontiers in endocrinology · 2023Article
- Article
- Mitochondria and the future of RASopathies: the emergence of bioenergetics.The Journal of clinical investigation · 2022Article
- Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway.Frontiers in pharmacology · 2022Article
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23 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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