Peripheral mitochondrial function in multiple organ dysfunction syndrome

Abstract

Multiple organ dysfunction syndrome (MODS) is the predominant cause of death in intensive care units worldwide but treatment remains supportive. Although mitochondrial dysfunction is thought to occur in sepsis related MODS, mitochondrial function in MODS remains poorly understood. An important barrier has been the requirement for organ biopsies to measure mitochondrial function because performing organ biopsies in patients with MODS poses significant risk of fatal bleeding and infection. A peripheral marker of mitochondrial function was therefore required. The hypotheses were that mitochondrial function can be measured from peripheral blood mononuclear cells, changes through the disease course and reflects disease severity in MODS. The aims were to develop an assay of mitochondrial function from peripheral blood and to apply it in patients in MODS through their disease course. Mitochondrial respiration assay was developed in the laboratory using peripheral blood from healthy volunteers and healthy male Wistar rats. The assay was used in experimental models of hypertension and mild acute pancreatitis and in a clinical trial of mild acute pancreatitis. Finally, peripheral blood mitochondrial function was measured daily during the first week, at three weeks and at six months in patients with MODS. Mitochondrial function from peripheral blood changed over the course of disease in MODS. Mitochondrial reactive oxygen species increased early and was followed by a decrease in mitochondrial respiration in MODS. Temporal mitochondrial respiration negatively correlated with temporal organ failure scores and mitochondrial respiration did not discriminate between septic and non septic causes of MODS. Mitochondrial respiration and mitochondrial superoxide correlated with each other throughout the first week. There were persistent features of mitochondrial dysfunction in septic MODS at six months. Multiple aspects of mitochondrial dysfunction occurred in patients with MODS and correlated with the severity of MODS. The results imply that shutting down mitochondrial respiration may be an adaptive response in MODS and manipulating mitochondrial respiration in MODS may be beneficial. The results from testing the assay in other disease states enabled a broader understanding of mitochondrial function in MODS. These findings have opened up several avenues for further clinical and laboratory research.