title: Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production.
abstract: Signal transducer and activator of transcription 3 (STAT3) is associated with various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria, where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that the amounts of STAT3 in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended on phosphorylation of Ser727in STAT3 and new protein synthesis. Under these conditions, mitochondrially localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the amino terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially localized STAT3 in sensing and responding to external stimuli.
authors.affiliation: Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA.|Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jeremy A
authors.identifier: http://orcid.org/0000-0001-6321-5971
authors.initials: JA
authors.lastname: Meier
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Moonjung
authors.identifier: http://orcid.org/0000-0003-3320-9815
authors.initials: M
authors.lastname: Hyun
authors.affiliation: Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA.|Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Cantwell
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.|Division of Surgical Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Ali
authors.identifier: http://orcid.org/0000-0001-8042-4548
authors.initials: A
authors.lastname: Raza
authors.affiliation: Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mertens
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Vidisha
authors.identifier: http://orcid.org/0000-0003-1808-6511
authors.initials: V
authors.lastname: Raje
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sisler
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Erin
authors.identifier: http://orcid.org/0000-0001-6523-4156
authors.initials: E
authors.lastname: Tracy
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Torres-Odio
authors.affiliation: Experimental Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.affiliation: School of Life Sciences, University of Nottingham, Nottingham, U.K.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Shaw
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Heinz
authors.initials: H
authors.lastname: Baumann
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.|Division of Surgical Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.|Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.|Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA.
authors.forename: Kazuaki
authors.identifier: http://orcid.org/0000-0002-6435-4241
authors.initials: K
authors.lastname: Takabe
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA. andrew.larner@vcuhealth.org.
authors.forename: Andrew C
authors.identifier: http://orcid.org/0000-0002-9543-4412
authors.initials: AC
authors.lastname: Larner
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D015850:Interleukin-6; D024101:Mitochondrial Proteins; D016877:Oxidants; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D006861:Hydrogen Peroxide; D021983:Cyclophilins