title: Reduction of STAT3 expression induces mitochondrial dysfunction and autophagy in cardiac HL-1 cells.
abstract: Signal transducer and activator of transcription 3 (STAT3) is an important mediator of cardiac survival pathways. Reduced levels of STAT3 in patients with end-stage heart failure suggest a clinical relevance of STAT3 deficiency for cardiac disease. The recent identification of STAT3 as a mitochondrial protein which is important for full activity of mitochondrial complex I has opened a new field for the investigation of how STAT3 functions in cardioprotection. The goal of this study was to establish a cell culture model with a reduced STAT3 expression, and to use this model for the investigation of mitochondrial and mitochondrial-associated functions under STAT3 deficiency. In the murine cardiomyogenic cell line HL-1, the expression of STAT3 was silenced by lentiviral transduction with anti-STAT3 shRNA (STAT3 KD cells). STAT3 mRNA and protein levels were significantly reduced in HL-1 STAT3 KD cells compared to HL-1 cells transduced with a control shRNA. Spectrophotometric and polarographic assays with mitochondrial enriched fractions and intact cells showed reduced activities of respiratory chain complexes I, II, III and IV in HL-1 STAT3 KD cells. At ultrastructural level, a severe damage of mitochondrial integrity was observed, combined with a significant increase in autophagolysosomes in STAT3-deficient HL-1 cells. Our results demonstrate that the HL-1 STAT3 KD cell line is a good model to study cellular consequences of STAT3 deficiency. Moreover, this is the first study to show that STAT3 deficiency leads to a disruption of mitochondrial ultrastructure and increased autophagy.
authors.affiliation: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neubergstr. 1, D-30625 Hannover, Germany. elschami.myriam@mh-hannover.de
authors.forename: Myriam
authors.initials: M
authors.lastname: Elschami
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Brigitte
authors.initials: B
authors.lastname: Philippens
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002460:Cell Line; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D009206:Myocardium / Q000166:cytology / Q000648:ultrastructure; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I