Mutation of mitochondrial ATP8 gene improves hepatic energy status in a murine model of acute endotoxemic liver failure.

Autor: Eipel C; Institute for Experimental Surgery, University of Rostock, Schillingallee 69 a, 18055 Rostock, Germany. christian.eipel@uni-rostock.de, Hildebrandt A, Scholz B, Schyschka L, Minor T, Kreikemeyer B, Ibrahim SM, Vollmar B
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2011 Feb 14; Vol. 88 (7-8), pp. 343-9. Date of Electronic Publication: 2010 Dec 15.
DOI: 10.1016/j.lfs.2010.12.011
Abstrakt: Aims: 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.
Main 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.
Key Findings: 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.
Significance: 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.
(Copyright © 2010 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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