Inflammation is a fundamental feature of many diseases. It is part of a programmed response to threats concerning an organism's integrity. Programming is modified by the environment and is made up of complex relationships between regulating mechanisms of metabolism. In this study, S. cerevisiae were used to establish a model of reprogramming, utilizing in this case a 23-h water-only fast compared to a standard high glucose environment. Crude mitochondrial preparations were made using differential centrifugation. Pyruvate Dehydrogenase Complex (PDC) activity was approximated via an assay measuring changes in ability to produce NADH. Experiments with lipopolysaccharide (LPS) involved a procedure exposing the yeast to LPS (100 ng/ml) for 90 min prior to mitochondrial isolation. Oxygen consumption rates were measured using a Clark type electrode setup. Results suggest that fasting in water can reprogram yeast mitochondria. Mechanisms modified by this process appear to regulate the ability of the mitochondria to maintain the relationship of oxygen consumption (indicative of electron transport) to RCR (indicative of membrane potential), largely separate to ATP synthesis. Although the ADP/O may be lower in the progeny of the fasted yeast, it is the fact that it maintained a higher RCR with the same or lower ADP/O, that is the important observation. Based on estimations of PDC activity, the progeny of the high glucose exposed yeast appeared less able to readily utilize pyruvate for respiration. In addition, the LPS challenge also revealed possible changes in immune response that may be resulting from glucose toxicity. In conclusion, S. cerevisiae can be reprogrammed to metabolically respond differently to a specific environment. This includes both a high glucose environment and a high glucose environment containing LPS (a pathogen associated molecular pattern), with regard to bioenergetic changes. These changes are associated in mammalian cells with the switch to a proinflammatory and proliferative metabolic state, analogous to that of M1 macrophages (decreased OxPhos and lower RCR), seen in atherosclerosis and other conditions. This data supports the use of this model for further investigation of proinflammatory processes and potential interventions to restore proper regulation of immune responses.

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Journal Article

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Friedman NS, De Britto GJ, Lehner AN

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