Reduction of STAT3 expression induces mitochondrial dysfunction and autophagy in cardiac HL-1 cells

Eur J Cell Biol. 2013 Jan;92(1):21-9. doi: 10.1016/j.ejcb.2012.09.002. Epub 2012 Oct 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / genetics
  • Cell Line
  • Electron Transport
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex IV / metabolism
  • Gene Expression Regulation
  • Gene Silencing
  • Mice
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Heart / ultrastructure
  • Myocardium / cytology
  • Myocardium / ultrastructure
  • RNA, Small Interfering
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*

Substances

  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Electron Transport Complex IV
  • Electron Transport Complex I