title: Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability.
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.
authors.affiliation: 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.
authors.forename: Fouad A
authors.initials: FA
authors.lastname: Zouein
authors.affiliation: 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.
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Duhé
authors.affiliation: 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.
authors.forename: Istvan
authors.initials: I
authors.lastname: Arany
authors.affiliation: Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Shirey
authors.affiliation: Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Hosler
authors.affiliation: Department of Neurology, The University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Sciences, Lebanese University, Rafic Hariri Educational Campus, Hadath, Lebanon.
authors.forename: Iman
authors.initials: I
authors.lastname: Saad
authors.affiliation: 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.
authors.forename: Mazen
authors.initials: M
authors.lastname: Kurdi
authors.affiliation: 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.
authors.forename: George W
authors.initials: GW
authors.lastname: Booz
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D053148:Caspase 3
keywords: Cell death; Mitochondria; NFκB; Reactive oxygen species; Tumor necrosis factor alpha