title: Mutation of mitochondrial ATP8 gene improves hepatic energy status in a murine model of acute endotoxemic liver failure.
abstract: OBJECTIVE
  Mitochondria not only generate and modulate bioenergy but also serve as biosensors for oxidative stress, and eventually become effector organelles for cell viability. Therefore, the implications of mitochondrial (dys)function in the development of multiple organ failure are profound. We investigated whether a mutation in the ATPase subunit-8 gene affects the course of endotoxemic acute liver failure.
  
  
  METHODS
  C57BL/6J (ATP8 wild type) and C57BL/6J-mt(FVB/N) (ATP8 mutant) mice were challenged with d-galactosamine (GalN) and Escherichia coli lipopolysaccharide (LPS) for induction of acute liver failure, and studied 6 h thereafter. Control mice received physiological saline only. Analysis included in vivo fluorescence microscopy of hepatic microcirculation and levels of hepatocellular apoptosis, hepatic adenosine nucleotides and oxidative stress. Additionally, survival rates were assessed.
  
  
  RESULTS
  Induction of endotoxemic liver failure provoked marked liver damage, which was coexistent with a drop of total adenosine nucleotide levels and increased oxidative stress. Of interest, oxidative stress was higher in the GalN/LPS challenged ATP8 mutants compared to wild types. Concomitantly, adenosine triphosphate (ATP) levels in livers of mice carrying the ATP8 mutation remained higher than those in wild type mice. As net result, ATP8 mutants showed lower transaminase release and a tendency to better survival rate upon GalN/LPS exposure compared to wild types.
  
  
  CONCLUSIONS
  Our findings demonstrate that mutation in the ATPase subunit-8 partially protects mice against endotoxemic stress, most probably due to better hepatic energy status despite elevated oxidative stress. Thus, modulating mitochondrial function to preserve bioenergetic status may be an effective strategy to protect against sepsis-induced multiorgan dysfunction.
authors.affiliation: Institute for Experimental Surgery, University of Rostock, Schillingallee 69 a, 18055 Rostock, Germany. christian.eipel@uni-rostock.de
authors.forename: Christian
authors.initials: C
authors.lastname: Eipel
authors.forename: Anke
authors.initials: A
authors.lastname: Hildebrandt
authors.forename: Birte
authors.initials: B
authors.lastname: Scholz
authors.forename: Lilianna
authors.initials: L
authors.lastname: Schyschka
authors.forename: Thomas
authors.initials: T
authors.lastname: Minor
authors.forename: Bernd
authors.initials: B
authors.lastname: Kreikemeyer
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004731:Endotoxins / Q000494:pharmacology; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D050259:Genes, Mitochondrial / Q000235:genetics* / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D017114:Liver Failure, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology
chemical_list: D004731:Endotoxins; C044101:endotoxin, Escherichia coli; D025261:Mitochondrial Proton-Translocating ATPases; C546989:mt-Atp8 protein, mouse