Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability

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• 作者：Fouad A. Zouein ; Roy J. Duh茅 ; Istvan Arany ; Kristin Shirey ; Jonathan P. Hosler ; Huiling Liu ; Iman Saad ; Mazen Kurdi ; George W. Booz
• 关键词：Tumor necrosis factor alpha ; Reactive oxygen species ; Cell death ; Mitochondria ; NF魏B
• 刊名：Cytokine
• 出版年：March, 2014
• 年：2014
• 卷：66
• 期：1
• 页码：7-16
• 全文大小：1866 K

文摘

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, TNF伪 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 I魏B伪 degradation with TNF伪. However, in the absence of STAT3 nuclear accumulation of NF魏B p65 with TNF伪 was attenuated and induction of the survival protein c-FLIP_L was eliminated. Nonetheless, WT MEF were more sensitive to TNF伪-induced death which was attributed to necrosis. Deletion of STAT3 decreased ROS formation induced by TNF伪 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.