Transcriptional reprogramming of metabolic pathways in critically ill patients

Abstract

BackgroundCritical illness causes a shift away from mitochondrial metabolism towards a greater dependence on glycolysis. This metabolic shift is thought to be associated with lactic acidosis, organ dysfunction and poor clinical outcomes. The current paradigm is that low oxygen supply causes regional hypoxia, which in turn drives such a metabolic shift. In this study, we evaluated whether the shift towards glycolysis can also occur in cells where oxygen supply is plentiful.MethodsWe used circulating blood cells from non-hypoxic critically ill patients (n = 47) as a model to study cellular metabolism in a normal oxygen milieu. We measured the transcriptomic profiles of canonical metabolic pathways in these cells and compared them to cells obtained from healthy controls (n = 18).ResultsTranscriptomic profiling revealed a significant reprogramming of metabolic pathways during critical illness. In well-oxygenated cells, there was a reduced expression of tricarboxylic acid cycle genes and genes associated with pyruvate entry into the mitochondria suggesting decreased mitochondrial oxidation. In contrast, glycolysis was accelerated, as reflected by an up-regulation of genes coding for enzymes of early and late glycolytic pathway that were associated with increased lactate production. The pentose phosphate pathway genes for NADPH production were also up-regulated suggesting enhanced antioxidant production during increased oxidative stress.ConclusionsContrary to the established paradigm, aerobic glycolysis does occur in non-hypoxic cells during critical illness and its occurrence may represent an adaptive strategy common to cells under increased oxidative stress. Further study of this previously under-recognized metabolic phenomenon might identify novel drug target for antioxidant therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-016-0094-1) contains supplementary material, which is available to authorized users.

Urine metabolomics in neonates with late-onset sepsis in a case-control study

“…Moreover, previous studies in adults documented the significance of elevated serum lactate as predictors of in-hospital mortality in infected-septic patients34. Alternatively, elevated lactate may represent decreased mitochondrial oxidative metabolism (oxidative phosphorylation) described in critically-ill patients35. Defective operation of the citric acid (Krebs) cycle in sepsis36 could also explain significantly lower concentrations of two of its intermediates alpha-ketoglutaric acid and fumarate in our group of septic infants compared to controls.…”

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“…Nalos et al used transcriptomic analysis to examine the cellular metabolism of circulating blood cells from nonhypoxic critically ill patients and observed a significant reprogramming of metabolic pathways during critical illness. These authors concluded that aerobic glycolysis does exist in nonhypoxic cells during critical illness ( 62 ). The increased lactate production may also indicate a metabolic shift to an inflammatory glycolysis.…”