title: A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction.
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 8 mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-alpha 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 8 h 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.
authors.affiliation: Department of Natural Sciences, Veterinary University Vienna, Vienna, Austria.
authors.forename: J Catharina
authors.initials: JC
authors.lastname: Duvigneau
authors.forename: Christina
authors.initials: C
authors.lastname: Piskernik
authors.forename: Susanne
authors.initials: S
authors.lastname: Haindl
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kloesch
authors.forename: Romana T
authors.initials: RT
authors.lastname: Hartl
authors.forename: Maik
authors.initials: M
authors.lastname: Hüttemann
authors.forename: Icksoo
authors.initials: I
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebel
authors.forename: Rudolf
authors.initials: R
authors.lastname: Moldzio
authors.forename: Manfred
authors.initials: M
authors.lastname: Gemeiner
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kozlov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004731:Endotoxins / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D007501:Iron; D006419:Heme Oxygenase (Decyclizing)