title: Mitochondrial-targeted Signal transducer and activator of transcription 3 (STAT3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species.
abstract: Expression of the STAT3 transcription factor in the heart is cardioprotective and decreases the levels of reactive oxygen species. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain. However, it has not been explored whether mitochondrial STAT3 modulates cardiac function under conditions of stress. Transgenic mice with cardiomyocyte-specific overexpression of mitochondria-targeted STAT3 with a mutation in the DNA-binding domain (MLS-STAT3E) were generated. We evaluated the role of mitochondrial STAT3 in the preservation of mitochondrial function during ischemia. Under conditions of ischemia heart mitochondria expressing MLS-STAT3E exhibited modest decreases in basal activities of complexes I and II of the electron transport chain. In contrast to WT hearts, complex I-dependent respiratory rates were protected against ischemic damage in MLS-STAT3E hearts. MLS-STAT3E prevented the release of cytochrome c into the cytosol during ischemia. In contrast to WT mitochondria, ischemia did not augment reactive oxygen species production in MLS-STAT3E mitochondria likely due to an MLS-STAT3E-mediated partial blockade of electron transport through complex I. Given the caveat of STAT3 overexpression, these results suggest a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor.
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Szczepanek
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.forename: Marta
authors.initials: M
authors.lastname: Derecka
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Qifang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szelag
authors.forename: Joanna
authors.initials: J
authors.lastname: Cichy
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Larner
mesh_terms: D000818:Animals; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000235:genetics; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D045304:Cytochromes c; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I