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.
Highlights
Critical illness causes a shift away from mitochondrial metabolism towards a greater dependence on glycolysis
Pathway analysis We focused our analysis on genes involved in the canonical metabolic pathways of glycolysis, tricarboxylic acid cycle and pentose phosphate pathway
Statistical analysis We focused our analysis on genes involved in the canonical metabolic pathways of glycolysis, tricarboxylic acid cycle and pentose phosphate pathway
Summary
Critical 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. Energy production from carbohydrate substrates is predominantly driven by mitochondrial oxidation and to a lesser extent by glycolysis. In times of increased physiological stress, this mitochondrial/cytosol balance is reversed favouring glycolysis as the dominant form of energy production [1]. Critical illness represents the most severe form of physiological stress to the human host. Stressed leukocytes in septic patients, for example, shift from mitochondrial oxidation to an increased dependence on glycolysis to meet their extraordinarily high metabolic demand (e.g. respiratory burst or phagocytosis) [2]. The physiological trigger for this metabolic shift, is largely unknown.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
