Release of the mitochondrial enzyme carbamoyl phosphate synthase under septic conditions

Abstract

To identify sepsis-related dysregulations of protein expression in the liver, we used a baboon model of acute endotoxemia and performed comparative proteome analysis. Treatment with lipopolysaccharide (LPS) was followed by an early but long-lasting (5-48 h) generation of N-terminal fragments of carbamoyl phosphate synthase-1 (CPS-1), an abundant enzyme of the hepatic urea cycle, which is normally located in the mitochondrial matrix. In addition, we developed a new sandwich immunoassay to determine circulating CPS-1 in human and baboons. We found CPS-1 to be induced by LPS and to be released into the circulation of healthy humans and baboons as early as 4 to 5 h after stimulation. Similarly, CPS-1 levels increased after injection of gram-positive bacteria in another baboon model. Enhanced CPS-1 levels were also detected in serum of patients with sepsis. Our data demonstrate fragmentation of CPS-1 in the liver and early increase in circulating CPS-1 levels under septic conditions. We suggest that circulating CPS-1 might serve as a novel serum marker indicating mitochondrial impairment of the liver and/or the small intestine in critically ill patients.