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Updated: May 2, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell
Fouad A Zouein1, Roy J Duhé2, Istvan Arany3
1Departments 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.
Abstract:
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.
Insights
Signal transducer and activator of transcription 3 (STAT3) is crucial for cellular response to stress and maintaining mitochondrial function. STAT3 deficiency impairs mitochondrial respiration and increases cell death, highlighting its role in cell viability.
Area of Science:
- Cellular Biology
- Mitochondrial Function
- Signal Transduction
Background:
- Signal transducer and activator of transcription 3 (STAT3) has been linked to mitochondrial function, but its physiological significance remains unclear.
- Tumor necrosis factor-alpha (TNFα) and serum deprivation are stimuli known to increase mitochondrial reactive oxygen species (ROS) production.
Purpose of the Study:
- To investigate the physiological role of STAT3 in the cellular response to TNFα and serum deprivation, focusing on its impact on mitochondrial function and cell viability.
- To elucidate the mechanisms by which STAT3 influences cellular responses to oxidative stress and pro-apoptotic stimuli.
Main Methods:
- Utilized wild-type (WT) and STAT3 knockout (KO) mouse embryonic fibroblasts (MEFs) to compare cellular responses.
- Assessed TNFα receptor expression, IκBα degradation, NFκB p65 nuclear accumulation, and c-FLIPL induction.
- Measured mitochondrial ROS formation, mitochondrial complex I levels, respiration rates, cytochrome c release, and caspase 3 cleavage.
Main Results:
- STAT3 deletion attenuated NFκB p65 nuclear accumulation and eliminated c-FLIPL induction in response to TNFα.
- STAT3 deficiency decreased TNFα- and serum deprivation-induced ROS formation, lowered complex I levels, and reduced respiration rates.
- STAT3 KO cells exhibited increased cytochrome c release under oxidative stress and enhanced caspase 3 cleavage upon serum deprivation compared to WT cells.
Conclusions:
- STAT3 plays a critical role in maintaining mitochondrial integrity and function, particularly under stress conditions.
- STAT3 is essential for the expression of pro-survival genes, contributing to cell viability.
- The findings establish STAT3's importance in cellular defense mechanisms against mitochondrial dysfunction and death.
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