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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.
摘要：
SOS1消融会导致MEF中特定的缺陷表型，包括细胞内ROS水平升高。我们表明，线粒体靶向抗氧化剂MitoTEMPO恢复正常的内源性ROS水平，提示线粒体主要参与这种有缺陷的SOS1依赖性表型的产生。SOS1的缺失导致线粒体形状的特定改变，质量,与WT或SOS2-KO对应物相比，动力学伴随着功能失调的线粒体百分比更高，电子传递速率更低。SOS1缺陷的MEFs还表现出呼吸复合物的特定变化及其组装成线粒体超复合物，并不断降低呼吸速率。糖酵解,和ATP生产，以及对氧化能量代谢的底物偏好和对葡萄糖的生存依赖的独特模式。RASless细胞显示有缺陷的呼吸/代谢表型，让人想起SOS1缺陷的MEFs，这表明这些细胞的线粒体缺陷与SOS1-GEF对细胞RAS靶标的活性缺乏机制相关。我们的观察结果提供了SOS1与细胞氧化应激控制之间的直接机制联系，并表明SOS1介导的RAS激活是正确的线粒体动力学和功能所必需的。
