PUBLICATION
HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models
- Authors
- 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, P.E., Thambo, J.B., Levy, N., Herault, Y., Bellance, N., Dias Amoedo, N., Magdinier, F., Sorg, T., Lacombe, D., Rossignol, R.
- ID
- ZDB-PUB-220303-18
- Date
- 2022
- Source
- The Journal of Clinical Investigation 132(8): (Journal)
- Registered Authors
- Fontenille, Laura
- Keywords
- Bioenergetics, Metabolism
- MeSH Terms
-
- AMP-Activated Protein Kinases/genetics
- AMP-Activated Protein Kinases/metabolism
- Animals
- Costello Syndrome*/genetics
- Costello Syndrome*/metabolism
- Germ-Line Mutation*
- Homeostasis
- Humans
- Mice
- Proto-Oncogene Proteins p21(ras)*/genetics
- Proto-Oncogene Proteins p21(ras)*/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 35230976 Full text @ Journal of Clin. Invest.
Citation
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, P.E., Thambo, J.B., Levy, N., Herault, Y., Bellance, N., Dias Amoedo, N., Magdinier, F., Sorg, T., Lacombe, D., Rossignol, R. (2022) HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models. The Journal of Clinical Investigation. 132(8):.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping