Mark Wefers Bettink

Measuring mitochondrial oxygenation and respiration in vivo in a human endotoxemia model 6 107 Introduction Mitochondrial function is of pivotal importance in cellular function. Subtle changes in mitochondrial function over time are thought to play a role in the development of several chronic diseases like Alzheimer’s disease and type 2 diabetes[1]. Mitochondrial dysfunction is also implicated to play an important role during critical illness where oxygen demand, supply and consumption may be impaired. For example, in sepsis, where failure of microcirculation and a diminished mitochondrial function is related to development of multi-organ failure and death, irrespective of age [2,3]. Measuring the balance between supply and demand of cellular oxygen might aid clinical evaluation of sepsis or guide patient-based care protocols [4,5]. Direct, non-invasive measurement of the concentration of cellular oxygen and mitochondrial function in intact tissue reflects this balance between supply and demand of cellular oxygen levels[6]. Recently, the Cellular Oxygen METabolism (COMET) measuring system has been developed, which enables bedside measurement of mitochondrial oxygenation and respiration[7]. The COMET device measures cutaneous mitochondrial oxygen tension (mitoPO 2 ) over time. MitoPO 2 is measured by means of delayed fluorescence of mitochondrial protoporphyrin IX (PpIX)[8]. Microcirculatory flow can be stopped by applying pressure with the measuring probe on the skin, enabling the determination of the mitochondrial oxygen consumption (mitoVO 2 ) [9]. The mitoVO 2 measurement is a non-invasive technique to assess mitochondrial respiration in vivo . Using the COMET device, the technical feasibility to measure mitoPO 2 and mitoVO 2 in humans has been demonstrated in healthy volunteers [10]. Another research group recently showed little effect of physical activity on mitoPO 2 and mitoVO 2 measured with the COMET monitor [11]. In this study, we investigated the feasibility of the COMET system to detect changes in mitochondrial oxygenation and respiration during experimental human endotoxemia, a standardizedwell-controlled and reproduciblemodel of systemic inflammation elicited by administration of E. coli lipopolysaccharide (LPS)[12]. We chose to use this model because previous work in rats has shown that LPS administration exerts detrimental effects on the mitochondrial oxygen consumption in skin, which was unrelated to alterations in mitochondrial oxygen tension[13].