Research Article

Laboratory Investigation (2008) 88, 70–77; doi:10.1038/labinvest.3700691; published online 5 November 2007

A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction

J Catharina Duvigneau1, Christina Piskernik2, Susanne Haindl2, Burkhard Kloesch2, Romana T Hartl1, Maik Hüttemann3, Icksoo Lee3, Thomas Ebel4, Rudolf Moldzio1, Manfred Gemeiner1, Heinz Redl2 and Andrey V Kozlov2

  1. 1Department of Natural Sciences, Veterinary University Vienna, Vienna, Austria
  2. 2Ludwig-Boltzmann Institute for Clinical and Experimental Traumatology in the AUVA Research Center, Vienna, Austria
  3. 3Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
  4. 4Department of Pathobiology and Zoology, Veterinary University Vienna, Vienna, Austria

Correspondence: Dr AV Kozlov, PhD, Ludwig-Boltzmann Institute for Clinical and Experimental Traumatology in the AUVA Research Center, Donaueschingenstr. 23, A-1200 Vienna, Austria. E-mail: andrey.kozlov@vu-wien.ac.at

Received 10 May 2007; Revised 21 September 2007; Accepted 25 September 2007; Published online 5 November 2007.

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Abstract

Mitochondria are involved in the development of organ failure in critical care diseases. However, the mechanisms underlying mitochondrial dysfunction are not clear yet. Inducible hemoxygenase (HO-1), a member of the heat shock protein family, is upregulated in critical care diseases and considered to confer cytoprotection against oxidative stress. However, one of the products of HO-1 is Fe2+ which multiplies the damaging potential of reactive oxygen species catalyzing Fenton reaction. The aim of this study was to clarify the relevance of free iron metabolism to the oxidative damage of the liver in endotoxic shock and its impact on mitochondrial function. Endotoxic shock in rats was induced by injection of lipopolysaccharide (LPS) at a dose of 8mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-α and the liver necrosis marker aspartate aminotransferase were increased in blood, confirming inflammatory response to LPS and damage to liver tissue, respectively. The levels of free iron in the liver were significantly increased at 4 and 8h after onset of endotoxic shock, which did not coincide with the decrease of transferrin iron levels in the blood, but rather with expression of the inducible form of heme oxygenase (HO-1). The proteins important for sequestering free iron (ferritin) and the export of iron out of the cells (ferroportin) were downregulated facilitating the accumulation of free iron in cells. The temporarily increased concentration of free iron in the liver correlated with the temporary impairment of both mitochondrial function and tissue ATP levels. Addition of exogenous iron ions to mitochondria isolated from control animals resulted in an impairment of mitochondrial respiration similar to that observed in endotoxic shock in vivo. Our data suggest that free iron released by HO-1 causes mitochondrial dysfunction in pathological situations accompanied by endotoxic shock.

Keywords:

endotoxic shock, free iron, inflammation, lipopolysaccharide, mitochondria, transferrin

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