Eine Mutation innerhalb der ATP8-Synthase verbessert den hepatischen Energiestatus im murinen Modell des akuten septischen Leberversagens

Abstract

The (dys)function of mitochondria plays an important role in the development of multiple organ failure. 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 exerts effects on the course of endotoxemic acute liver failure in mice. For this purpose, wildtype and ATP8 mutant mice were challenged with D-galactosamine (GalN) and Escherichia coli lipopolysaccharide (LPS) and studied 6 hrs thereafter. Control mice received physiological saline only. Analysis included in vivo fluorescence microscopy of hepatic microcirculation and determination of hepatocellular apoptosis, levels of hepatic adenosine nucleotides as well as concentrations of plasma malondialdehyde as a marker of oxidative stress. Induction of endotoxemic liver failure provoked marked liver damage, characterized by microvascular perfusion failure and transaminase release. Of interest, oxidative stress was significantly higher in the GalN/LPS challenged ATP8 mutants compared to wild types. In contrast, the ATP/ADP ratio in livers of mice carrying the ATP8 mutation remained significantly higher than those in wild type mice. As a net result, ATP8 mutant mice showed lower transaminase release and better survival rate compared to wild types. Our data demonstrate that mutation in the ATPase subunit 8 partially protects mice under endotoxemic stress conditions most probably due to better hepatic energy status despite elevated overall oxidative stress. These findings underline the role of genetic polymorphisms in the pathophysiology of sepsis.