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Metabolomics Profiling Reveals Differential Adaptation of Major www.nature.com/scientificreports Correction: Author Correction OPEN Metabolomics profling reveals diferential adaptation of major energy metabolism pathways Received: 19 May 2017 Accepted: 2 January 2018 associated with autophagy upon Published online: 05 February 2018 oxygen and glucose reduction Katja Weckmann1, Philip Diefenthäler1, Marius W. Baeken1, Kamran Yusifi1, Christoph W. Turck2, John M. Asara3, Christian Behl1 & Parvana Hajieva1 The ability of cells to rearrange their metabolism plays an important role in compensating the energy shortage and may provide cell survival. Our study focuses on identifng the important adaptational changes under the conditions of oxygen and glucose reduction. Employing mass spectrometry-based metabolomics in combination with biochemistry and microscopy techniques we identifed metabolites, proteins and biomolecular pathways alterations in primary human IMR90 fbroblasts upon energy defcits. Multivariate statistical analyses revealed signifcant treatment-specifc metabolite level and ratio alterations as well as major energy metabolism pathways like ‘glycolysis’, ‘pentose phosphate pathway’, ‘mitochondrial electron transport chain’ and ‘protein biosynthesis (amino acids)’ indicating an activation of catabolism and reduction of anabolism as important mechanisms of adaptation towards a bioenergetic demand. A treatment-specifc induction of the autophagic and mitophagic degradation activity upon oxygen reduction, glucose reduction as well as oxygen-glucose reduction further supports our results. Therefore, we suggest that the observed alterations represent an adaptive response in order to compensate for the cells’ bioenergetics needs that ultimately provide cell survival. A number of pathological conditions are accompanied by cellular bioenergetic perturbations mainly triggered by oxygen reduction (OR) and glucose reduction (GR). For instance, energy imbalances observed by unexplained weight loss is a frequently observed clinical fnding for patients sufering from cancer, heart failure, Alzheimer’s and Parkinson’s disease1. However, the basic bioenergetic adaptation mechanism remains elusive. Adaptation to glucose and oxygen reduction requires biochemical and genetic responses culminating in an acute and/or chronic metabolic rearrangement in order to meet the cells’ bioenergetic needs. Multiple pathways may alter under nutrient stress, as glucose and oxygen are the major regulators of the cellular core metabolism. Eukaryotic cells seem to generally adapt to nutrient deprivation by modifying glycolytic and mitochondrial metabolism that are important entities of the cellular core metabolism2. However, the decisive adaptive pathways ensuring cell survival remain elusive. Oxygen and glucose are essential for the mitochondrial energy metabolism in order to generate energy in form of adenosine triphosphate (ATP) through the oxidative phosphorylation (OXPHOS). Ischemia, tissue dam- age and poorly vascularized cancer can restrict oxygen supply leading to metabolic stress and potentially apopto- sis3. AMP activated protein kinase (AMPK) is the major energy status sensor that promotes and inhibits catabolic and anabolic pathways, respectively, to generate ATP. High AMP and ADP levels activate the AMPK, whereas increased levels of ATP inhibit the enzyme4–8. Te mammalian target of rapamycin (mTOR) is a central regu- latory nexus that integrates physiological signals from diferent cellular signaling cascades, thereby modulating 1Institute of Pathobiochemistry, Johannes Gutenberg University, Medical School, Duesbergweg 6, 55099, Mainz, Germany. 2Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2–10, 80804, Munich, Germany. 3Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Correspondence and requests for materials should be addressed to P.H. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:2337 | DOI:10.1038/s41598-018-19421-y 1 www.nature.com/scientificreports/ anabolic versus catabolic pathways in response to nutrients, growth factors, and the cellular energy status. mTOR controls several metabolic pathways at the transcriptional, translational, and posttranslational level including ‘glycolysis’, the ‘pentose phosphate pathway’, and OXPHOS by positively modulating mitochondrial biogenesis and activity9–12. Enhanced autophagic and mitophagic activity bufer metabolic stress most likely by degrading intracellular energy reserves like lipids, glycogen, and proteins to generate amino acids, nucleotides, fatty acids, and sugars that are recycled into metabolic pathways13. Tus, autophagy and mitophagy also contribute in maintaining the cellular energy balance. Another bioenergetic adaptive response is mostly described for cancer cells in hypoxic microenvironments: Warburg frstly proposed a metabolic reprogramming from oxidative phosphorylation (OXPHOS) to aerobic glycolysis in order to produce ATP and metabolic intermediates14. Terefore, changes in glucose and oxygen availability induce an adaptive response that may allow for extended survival. Metabolomics profling analysis is an important tool to generate a cellular metabolic fngerprint under stress conditions. Alterations provide signifcant and novel knowledge towards the cells’ metabolism adjustment to counter-balance the energy defect15–18. In our present study, we aim to analyze the crosstalk between the energy homeostasis with mitophagy and autophagy. We employed primary human IMR90 fibroblasts to investigate the effect of OR, GR and oxygen-glucose reduction (OGR) by metabolomics profling analyses, biochemical and microscopic analyses. Our goal was to identify signifcantly altered metabolite levels and ratios, enriched biochemical pathways and biosignatures responsible for the restoration of the cellular energy demand providing cell survival. Our study demonstrates that cells deprived in GR, OR and OGR demonstrate a treatment-specifc pattern of metabolic changes, which manifests by altering major energy metabolism pathways. Moreover, our metabolomics profling approach reveals a diferential treatment-induced adaptation mechanism associated with autophagy and mitophagy. Results Cell survival analysis. Glucose and oxygen are major energy sources and regulators of metabolism. Terefore, a long-term withdrawal of glucose and oxygen may have an impact on cell morphology and survival in cell culture conditions. Microscopic examination of cells afer 24 h of OR, GR and OGR revealed no signifcant changes in morphology. Western blotting analysis of the cleaved Caspase 3, a well-established marker of apopto- sis, revealed no signs of apoptosis upon OR, GR and OGR (Fig. S1). Metabolomics profling analyses. Altogether 292, 287 and 292 metabolites were quantifed in primary human IMR90 fbroblasts comparing OR, GR and OGR with control, respectively (Table S1). We combined three diferent standard multivariate statistical methods to achieve robust metabolomics results. Generally, statistical tests including principal component analyses (PCA), partial least squares-discriminant analysis (PLS-DA) and signifcance analysis of microarrays and other -omics datasets (SAM) are employed in order to analyze metab- olite profles. PCA and PLS-DA are statistical tests in order to analyze treatment patterns and group separa- tion. Additionally, the PLS-DA variable infuence of projection (VIP)-score ranks metabolites according to their importance for group separation. SAM can be employed to analyze statistical signifcant metabolites comparing diferent treatment groups. In the present study, metabolite profles separated control from OR, GR and OGR in the PCA and PLS-DA (Fig. 1). We further assessed the quality of the data by calculating Q2 values indicating good and predictive PLS-DA models for OR, GR and OGR (OR: Q2 = 0.68, R2 = 1.00, Accuracy = 0.90; GR: Q2 = 0.87, R2 = 1.00, Accuracy = 1.00; OGR: Q2 = 0.87, R2 = 1.00, Accuracy = 1.00). Additionally, 45, 47 and 89 metabolites were signifcantly altered in OR, GR and OGR, respectively. For OR 19 and 26, GR 15 and 32, and OGR 45 and 44 metabolites were up- and downregulated, respectively (Tables S2–S4). Furthermore, we analyzed overlapping metabolites for all conditions. Terefore, we compared signifcantly up- and downregulated metabolites of each treatment with a VENN-diagram. Interestingly, there was no overlap for OR and GR observed for the signifcantly up-regulated metabolites. Decreased metabolites were overlapping for all conditions. However, OR seems to be largely difering from GR: Although OR shares 7 and 13 metabolites with GR and OGR, respectively, GR shares 27 metabolites with OGR (Fig. S2). Next, the statistically signifcant altered up- and downregulated metabolites from OR, GR and OGR were interrogated for overrepresented (enriched) biomolecular pathways. OR-upregulated metabolites statistically signifcant enriched the ‘pentose phosphate pathway’ and ‘glycolysis’, whereas OR-downregulated metabolites did not statistically enrich any pathways. Furthermore, the ‘aspartate metabolism’ was enriched and upregulated upon GR, whereas ‘gluconeogenesis’, ‘glycolysis’, ‘pentose phosphate pathway’, ‘glycerol phosphate shuttle’, ‘mitochondrial electron transport chain’, ‘fructose and mannose degrada- tion’ and ‘nucleotide sugars metabolism’ were signifcantly overrepresented and decreased. OGR showed a sig- nifcant enrichment
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