Suppression of mitochondrial ATPase inhibitor protein (IF1) in the liver of late septic rats

Abstract

Sepsis and ensuing multiple organ failure continue to be the most leading cause of death in critically ill patients. Despite hepatocyte-related dysfunctions such as necrosis, apoptosis as well as mitochondrial damage are observed in the process of sepsis, the molecular mechanism of pathogenesis remains uncertain. We recently identified one of the differentially expressed genes, mitochondrial ATPase inhibitor protein (IF1) which is down-regulated in late septic liver. Hence, we further hypothesized that the variation of IF1 protein may be one of the causal events of the hepatic dysfunction during late sepsis. The results showed that the elevated mitochondrial F0F1-ATPase activity is concomitant with the decline of intramitochondrial ATP concentration in late septic liver. In addition, the key finding of this study showed that the mRNA and the mitochondrial content of IF1 were decreased in late sepsis while no detectable IF1 was found in cytoplasm. When analyzed by immunoprecipitation, it seems reasonable to imply that the association capability of IF1 with F1-ATPase beta-subunit is not affected. These results confirm the first evidence showing that the suppression of IF1 expression and subsequent elevated mitochondrial F0F1-ATPase activity might contribute to the bioenergetic failure in the liver during late sepsis.

Mitochondrial function in sepsis

“…Rats and mice were most often studied. The effects of LPS and faecal peritonitis/CLP on mitochondria are summarized in Fig.…”

Expression of genes belonging to the interacting TLR cascades, NADPH-oxidase and mitochondrial oxidative phosphorylation in septic patients

“…Commin et al observed that rats that suffered CLP showed decreased activity of complex I, but not of the complexes II, III and IV in the electron transport chains [ 38 ]. In contrast, increased consumption of oxygen and breathing efficiency was demonstrated in the livers of septic rats [ 39 ].…”

Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis

“…A decrease in ATP content of roughly 15% has also been described during long-term anesthesia in healthy animals (48), possibly related to decreased perfusion of skeletal muscle (49). Nevertheless, decreased tissue ATP concentrations in septic rodents and pigs have been described, and arguments for substrate deficiency, exaggerated ATP hydrolysis, and decreased mitochondrial mass presented (50)(51)(52). In critically ill patients with sepsis and multiple organ failure, skeletal muscle mitochondrial enzyme activities were reduced and concentrations of ATP and creatine phosphate decreased (53).…”