Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis
| Autor: | Rósula García-Navas, Fernando C. Baltanás, P. Liceras-Boillos, Nuria Calzada, José M. Cuezva, Eugenio Santos, Carmela Gómez, Cristina Nuevo-Tapioles |
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| Přispěvatelé: | UAM. Departamento de Biología Molecular, Instituto de Salud Carlos III, Junta de Castilla y León, Fundación Ramón Areces, European Commission, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, 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 |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Fission Molecular biology Activation Endogeny Oxidative phosphorylation Mitochondrion Biology medicine.disease_cause Mitochondrial Dynamics Article Induction 03 medical and health sciences 0302 clinical medicine Genetics medicine Homeostasis Glycolysis Fusion Pathways Cancer Cell-Proliferation Superoxide Metabolism Oncogenes Mass Biología y Biomedicina / Biología Electron transport chain Cell biology Oxidative Stress 030104 developmental biology 030220 oncology & carcinogenesis ras Guanine Nucleotide Exchange Factors Oxidative stress Intracellular Cell signalling |
| Zdroj: | Oncogene Digital.CSIC. Repositorio Institucional del CSIC instname Biblos-e Archivo. Repositorio Institucional de la UAM |
| ISSN: | 1476-5594 |
| Popis: | © The Author(s) 2021. 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. This work was supported by grants from ISCIII-MCUI (FIS PI19/00934 and CIBERONCCB16/12/00352), Junta de Castilla y Leon (SA264P18-UIC 076), and Ramon Areces Foundation (CIVP19A5942). The research was co-financed by FEDER funds. |
| Databáze: | OpenAIRE |
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