缺失 STAT3 的鼠胚胎成纤维细胞揭示了其对线粒体功能和细胞活力的双面作用。
Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability.
机构信息
Departments of Pharmacology and Toxicology, The University of Mississippi Medical Center, Jackson, MS, USA; School of Medicine and The Mississippi Center for Heart Research, The University of Mississippi Medical Center, Jackson, MS, USA; The Cardiovascular-Renal Research Center, The University of Mississippi Medical Center, Jackson, MS, USA.
Departments of Pharmacology and Toxicology, The University of Mississippi Medical Center, Jackson, MS, USA; Department of Radiation Oncology, The University of Mississippi Medical Center, Jackson, MS, USA; The Cancer Institute, The University of Mississippi Medical Center, Jackson, MS, USA.
出版信息
Cytokine. 2014 Mar;66(1):7-16. doi: 10.1016/j.cyto.2013.12.006. Epub 2013 Dec 31.
STAT3 has been implicated in mitochondrial function; however, the physiological relevance of this action is not established. Here we studied the importance of STAT3 to the cellular response to stimuli, TNFα and serum deprivation, which increase mitochondrial reactive oxygen species (ROS) formation. Experiments were performed using wild type (WT) and STAT3 knockout (KO) mouse embryonic fibroblasts (MEF). Both WT and STAT3 KO MEF expressed similar levels of tumor necrosis factor receptor 1 (TNFR1) and exhibited comparable IκBα degradation with TNFα. However, in the absence of STAT3 nuclear accumulation of NFκB p65 with TNFα was attenuated and induction of the survival protein c-FLIPL was eliminated. Nonetheless, WT MEF were more sensitive to TNFα-induced death which was attributed to necrosis. Deletion of STAT3 decreased ROS formation induced by TNFα and serum deprivation. STAT3 deletion was associated with lower levels of complex I and rates of respiration. Relative to WT cells, mitochondria of STAT3 KO cells released significantly more cytochrome c in response to oxidative stress and had greater caspase 3 cleavage due to serum deprivation. Our findings are consistent with STAT3 being important for mitochondrial function and cell viability by ensuring mitochondrial integrity and the expression of pro-survival genes.
STAT3 被认为与线粒体功能有关；然而，这种作用的生理相关性尚未确定。在这里，我们研究了 STAT3 对细胞对刺激（TNFα 和血清剥夺）反应的重要性，这些刺激会增加线粒体活性氧（ROS）的形成。实验使用野生型（WT）和 STAT3 敲除（KO）小鼠胚胎成纤维细胞（MEF）进行。WT 和 STAT3 KO MEF 均表达相似水平的肿瘤坏死因子受体 1（TNFR1），并表现出与 TNFα 相当的 IκBα 降解。然而，在没有 STAT3 的情况下，与 TNFα 结合的 NFκB p65 的核积累被减弱，并且诱导生存蛋白 c-FLIPL 被消除。尽管如此，WT MEF 对 TNFα 诱导的死亡更为敏感，这归因于坏死。STAT3 的缺失减少了 TNFα 和血清剥夺诱导的 ROS 形成。STAT3 的缺失与复合物 I 的水平和呼吸速率降低有关。与 WT 细胞相比，STAT3 KO 细胞的线粒体在氧化应激下释放出更多的细胞色素 c，并且由于血清剥夺导致更多的 caspase 3 切割。我们的研究结果表明，STAT3 通过确保线粒体完整性和生存基因的表达，对线粒体功能和细胞活力很重要。
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