HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models
Journal of Clinical Investigation. 2022-04-15; 132(8):
DOI: 10.1172/JCI131053
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1. J Clin Invest. 2022 Apr 15;132(8):e131053. doi: 10.1172/JCI131053.
HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis
in Costello syndrome models.
Dard L(1)(2)(3), Hubert C(1)(2), Esteves P(1)(2), Blanchard W(1)(2)(3), Bou
About G(4), Baldasseroni L(5), Dumon E(1)(2), Angelini C(1)(2)(6), Delourme
M(5), Guyonnet-Dupérat V(2)(7), Claverol S(2)(8), Fontenille L(9), Kissa K(9),
Séguéla PE(2)(10)(11), Thambo JB(2)(10)(11), Nicolas L(5), Herault Y(4)(12),
Bellance N(1)(2), Dias Amoedo N(1)(2)(3), Magdinier F(5), Sorg T(4), Lacombe
D(1)(2)(6), Rossignol R(1)(2)(3).
Author information:
(1)INSERM U1211, Bordeaux, France.
(2)Bordeaux University, Bordeaux, France.
(3)CELLOMET, Functional Genomics Center, Bordeaux, France.
(4)Université de Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, Institut
Clinique de la Souris, Illkirch, France.
(5)Aix-Marseille University, INSERM, Marseille Medical Genetics, Marseille,
France.
(6)Medical Genetics Department, Bordeaux University Hospital, Bordeaux, France.
(7)Vect’UB, vectorology platform, INSERM US005 – CNRS UMS 3427-TBM-Core, and.
(8)Plateforme Proteome, University of Bordeaux, Bordeaux, France.
(9)AZELEAD, Montpellier, France.
(10)CHU Bordeaux, Haut-Lévèque Hospital, Cardiology Department, Bordeaux,
France.
(11)IHU LYRIC, Pessac, France.
(12)Université de Strasbourg, CNRS, INSERM Institut de Génétique et de Biologie
Moléculaire et Cellulaire, Illkirch, France.
Comment in
J Clin Invest. 2022 Apr 15;132(8):1-5. doi: 10.1172/JCI157560.
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.
DOI: 10.1172/JCI131053
PMCID: PMC9012293
PMID: 35230976 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: RR, DL, LD, and NDA report
a patent (PCT/EP2022/051382) on the use of the bezafibrate and urolithin A
pharmacological drug combination for the treatment of hypertrophic
cardiomyopathy in Costello syndrome.