4.8 Article

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

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 8, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI131053

Keywords

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Funding

  1. French Association of Costello Syndrome and Cardiofaciocutaneous Syndrome
  2. French National Research Agency (ANR) [ANR-15-CE17-0003]
  3. Institut National de la Sante et de la Recherche Medicale (INSERM)
  4. University of Bordeaux
  5. SATT Nouvelle-Aquitaine AST
  6. Agence Nationale de la Recherche (ANR) [ANR-15-CE17-0003] Funding Source: Agence Nationale de la Recherche (ANR)

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This study analyzed the molecular determinants of Costello syndrome and found that mitochondrial proteostasis and bioenergetics play a crucial role in the pathophysiology of the disease. The study suggests that patients with Costello syndrome may benefit from treatment with mitochondrial modulators.
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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