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

Fouad A Zouein; Roy J Duhé; Istvan Arany; Kristin Shirey; Jonathan P Hosler; Huiling Liu; Iman Saad; Mazen Kurdi; George W Booz

doi:10.1016/j.cyto.2013.12.006

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

Cytokine. 2014 Mar;66(1):7-16. doi: 10.1016/j.cyto.2013.12.006. Epub 2013 Dec 31.

Authors

Fouad A Zouein¹, Roy J Duhé², Istvan Arany³, Kristin Shirey⁴, Jonathan P Hosler⁴, Huiling Liu⁵, Iman Saad⁶, Mazen Kurdi⁷, George W Booz⁸

Affiliations

¹ 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.
² 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.
³ Department of Pediatrics, The University of Mississippi Medical Center, Jackson, MS, USA; The Cardiovascular-Renal Research Center, The University of Mississippi Medical Center, Jackson, MS, USA.
⁴ Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS, USA.
⁵ Department of Neurology, The University of Mississippi Medical Center, Jackson, MS, USA.
⁶ Department of Chemistry and Biochemistry, Faculty of Sciences, Lebanese University, Rafic Hariri Educational Campus, Hadath, Lebanon.
⁷ Departments of Pharmacology and Toxicology, The University of Mississippi Medical Center, Jackson, MS, USA; Department of Chemistry and Biochemistry, Faculty of Sciences, Lebanese University, Rafic Hariri Educational Campus, Hadath, Lebanon.
⁸ 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. Electronic address: gbooz@umc.edu.

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.

Keywords: Cell death; Mitochondria; NFκB; Reactive oxygen species; Tumor necrosis factor alpha.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caspase 3 / metabolism
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cell Respiration / drug effects
Cell Survival / drug effects
Cytochromes c / metabolism
Cytoprotection / drug effects
Embryo, Mammalian / cytology*
Fibroblasts / cytology*
Fibroblasts / drug effects
Fibroblasts / enzymology
Fibroblasts / metabolism*
Humans
Mice
Mice, Knockout
Mitochondria / drug effects
Mitochondria / metabolism*
Models, Biological
NF-kappa B / metabolism
Protein Binding / drug effects
Reactive Oxygen Species / metabolism
STAT3 Transcription Factor / deficiency*
STAT3 Transcription Factor / metabolism*
Signal Transduction / drug effects
Tumor Necrosis Factor-alpha / pharmacology

Substances

NF-kappa B
Reactive Oxygen Species
STAT3 Transcription Factor
Stat3 protein, mouse
Tumor Necrosis Factor-alpha
Cytochromes c
Caspase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding