Mitochondria and the future of RASopathies: the emergence of bioenergetics

Abstract

RASopathies are a family of rare autosomal dominant disorders that affect the canonical Ras/MAPK signaling pathway and manifest as neurodevelopmental systemic syndromes, including Costello syndrome (CS). In this issue of the JCI, Dard et al. describe the molecular determinants of CS using a myriad of genetically modified models, including mice expressing HRAS p.G12S, patient-derived skin fibroblasts, hiPSC-derived human cardiomyocytes, an HRAS p.G12V zebrafish model, and human lentivirally induced fibroblasts overexpressing HRAS p.G12S or HRAS p.G12A. Mitochondrial proteostasis and oxidative phosphorylation were altered in CS, and inhibition of the AMPK signaling pathway mediated bioenergetic changes. Importantly, the pharmacological induction of this pathway restored cardiac function and reduced the developmental defects associated with CS. These findings identify a role for altered bioenergetics and provide insights into more effective treatment strategies for patients with RASopathies.

Figure 1. Crosstalk among RAS/MAPK, PI3K/AKT-mTOR, and AMPK pathways in RASopathy-induced mitochondrial biogenesis.

(A) RASopathies are a group of developmental disorders that include CS. Ligands binding to tyrosine kinase receptors recruit proteins, such as GRB2 and SHP2, to the membrane and aid in the transactivation of guanine nucleotide exchange factors, such as son of sevenless (SOS). SOS catalyzes RAS activation to initiate signaling events involving the kinases RAF, MEK, ERK, and RSK. GTPase activating proteins hydrolyze GTP to GDP, which inactivates RAS GTPases and terminates downstream signaling. Crosstalk between the RAS/MAPK and PI3K/AKT-mTOR pathways can occur in a cell-type and stimulation-dependent manner. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis. In healthy cells, the three pathways crosstalk to balance energy availability with cellular function. RASopathy mutations impair the energy balance, altering AMPK protein expression levels and inducing aberrant posttranslational modifications. miR-221* may inhibit AMPK expression and serve as a downstream effector of RAS/MAPK signaling. (B) Under physiological conditions, the mitochondrial TCA cycle uses intermediates from catabolism of energy substrates, such as fatty acids, glucose, glutamine, and branched chain amino acids (BCAAs), to produce energy-rich FADH₂ and NADH, components for biosynthesis and OXPHOS. In RASopathies, mitochondrial ATP production may favor pyruvate derived from glycolysis over substrate derived from fatty acid oxidation (FAO). OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; α-KG, α-ketoglutarate. (C) Mitochondrial OXPHOS efficiently produces ATP. Electrons from electron donors FADH₂ and NADH flow through a series of protein complexes (I–IV) within the mitochondrial membrane and pump protons from the matrix and across the inner membrane. The electrochemical proton gradient generates free energy that is coupled with the synthesis of ATP from ADP and Pi by complex V (ATP synthase). Dysfunctional mitochondrial complexes in RASopathies lead to increased basal proton leaks, decreased ATP, and increased ROS production, resulting in HCM. Asterisks indicate RASopathy mutations.