Artículo
Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis
Autor/es | García Navas, Rósula
Liceras Boillos, Pilar Gómez Rodríguez, Carmela Calvo Baltanás, Fernando Calzada, Nuria Nuevo Tapioles, Cristina Cuezva Marcos, Jose Manuel Santos, Eugenio |
Departamento | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica |
Fecha de publicación | 2021-06-12 |
Fecha de depósito | 2022-12-15 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) Instituto de Salud Carlos III FIS PI19/00934; CIBERONC-CB16/12/00352 Gobierno regional de Castilla y Leon SA264P18-UIC 076 Fundación Ramon Areces CIVP19A5942 |
Identificador del proyecto | FIS PI19/00934
CIBERONC-CB16/12/00352 SA264P18-UIC 076 CIVP19A5942 |
Cita | García Navas, R., Liceras Boillos, P., Gómez Rodríguez, C., Calvo Baltanas, F., Calzada, N., Nuevo Tapioles, C.,...,Santos, E. (2021). Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis. Oncogene, 40 (27), 4538-4551. https://doi.org/10.1038/s41388-021-01886-3. |
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