Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Abstract

SOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function.

Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia

“…In an effort to produce further direct experimental evidence supporting the above hypothesis, in this report, we have evaluated the effect of specific SOS1 and/or SOS2 genetic ablation on a mouse model of p210 BCR/ABL -driven CML. For this purpose, we generated an ad hoc mouse colony resulting from cross-mating a known transgenic p210 BCR/ABL -driven CML mouse model [ 33 , 34 ] with our SOS1/2-KO system [ 19 , 26 , 35 ] (allowing us to generate WT, SOS1-KO, SOS2-KO, and SOS1/2-DKO mice). Using this combined {Tec-p210 BCR/ABL |SOS1/2-KO} genetic system, we investigated the phenotypic and functional effects of direct SOS1 and/or SOS2 ablation on the initiation/progression of CML in adult mice.…”

“…The combined {Tec-p210 BCR/ABL |SOS1/2-KO} mouse model used in this report was generated by performing relevant cross-matings ( Figure 1 A) between a transgenic mouse strain, kindly provided by Dr. Honda [ 33 ], and mice of appropriate genotypes from our TAM-inducible SOS1/2-KO colony [ 19 , 26 , 31 , 35 ]. As previously described [ 35 ] a mouse strain harboring a floxed version of SOS1 with exon 10, flanked by LoxP sites (Sos1 fl/fl ), was crossed with SOS2-KO mice [ 24 , 25 ] in order to generate our conditional SOS1/2-KO mouse model, where SOS1 ablation is controlled by CreERT2.…”

“…The ubiquitously expressed members of the SOS family (SOS1, SOS2) are the most universal and functionally relevant GEFs capable of activating RAS and RAC GTPases (and, consequently, their specific downstream signaling cascades) in a variety of biological contexts [ 18 , 19 , 20 , 21 , 22 , 23 ]. Whereas SOS1 is essential for embryonic development [ 24 ], SOS2 is dispensable to reach adulthood in mice [ 25 ].…”

“…We managed to bypass the embryonic lethality of SOS1-KO alleles by using a floxed, tamoxifen-inducible SOS1 null mutation that allowed the generation and parallel analysis of the adult, viable mice of four relevant SOS genotypes (WT, SOS1-KO, SOS2-KO, and SOS1/2-DKO). Using this genetic KO system, we recently demonstrated the functional prevalence of SOS1 over SOS2 regarding the control of MEF cellular proliferation and viability, as well as a direct mechanistic link between SOS1 and the control of intracellular mitochondrial redox homeostasis [ 19 , 26 ], and we also characterized the specific functional roles of SOS1 and SOS2 in different biological contexts [ 27 , 28 , 29 , 30 ].…”

Oxidative Stress in Arterial Hypertension (HTN): The Nuclear Factor Erythroid Factor 2-Related Factor 2 (Nrf2) Pathway, Implications and Future Perspectives

“…Aside from the peripheral effects, ROS can regulate blood pressure via central mechanisms. Mitochondrial superoxide is overproduced in conditions of activated renin–angiotensin system (RAS) in the central nervous system (CNS) [ 49 ]. More than that, the mitochondrial ROS activate Nrf2 and promote the expression of genes involved in the control of mitochondrial and antioxidant genes via various protein kinases [ 50 ].…”