Publications by authors named "Oscar Yanes"

73 Publications

Exploring the Use of Gas Chromatography Coupled to Chemical Ionization Mass Spectrometry (GC-CI-MS) for Stable Isotope Labeling in Metabolomics.

Anal Chem 2021 01 28;93(3):1242-1248. Epub 2020 Dec 28.

Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain.

Isotopic-labeling experiments have been valuable to monitor the flux of metabolic reactions in biological systems, which is crucial to understand homeostatic alterations with disease. Experimental determination of metabolic fluxes can be inferred from a characteristic rearrangement of stable isotope tracers (e.g., 13C or 15N) that can be detected by mass spectrometry (MS). Metabolites measured are generally members of well-known metabolic pathways, and most of them can be detected using both gas chromatography (GC)-MS and liquid chromatography (LC)-MS. In here, we show that GC methods coupled to chemical ionization (CI) MS have a clear advantage over alternative methodologies due to GC's superior chromatography separation efficiency and the fact that CI is a soft ionization technique that yields identifiable protonated molecular ion peaks. We tested diverse GC-CI-MS setups, including methane and isobutane reagent gases, triple quadrupole (QqQ) MS in SIM mode, or selected ion clusters using optimized narrow windows (∼10 Da) in scan mode, and standard full scan methods using high resolution GC-(q)TOF and GC-Orbitrap systems. Isobutane as a reagent gas in combination with both low-resolution (LR) and high-resolution (HR) MS showed the best performance, enabling precise detection of isotopologues in most metabolic intermediates of central carbon metabolism. Finally, with the aim of overcoming manual operations, we developed an R-based tool called isoSCAN that automatically quantifies all isotopologues of intermediate metabolites of glycolysis, TCA cycle, amino acids, pentose phosphate pathway, and urea cycle, from LRMS and HRMS data.
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http://dx.doi.org/10.1021/acs.analchem.0c02998DOI Listing
January 2021

Endogenous retroelement activation by epigenetic therapy reverses the Warburg effect and elicits mitochondrial-mediated cancer cell death.

Cancer Discov 2020 Dec 18. Epub 2020 Dec 18.

Division of Hematology-Oncology, Center for Applied Medical Research CIMA, University of Navarra, Pamplona, Spain

During millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anti-cancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing anti-viral responses that eliminate tumors through mechanisms not completely understood. Here we find that massive binding of epigenetically-activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2-family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1065DOI Listing
December 2020

Identification of metabolic changes leading to cancer susceptibility in Fanconi anemia cells.

Cancer Lett 2020 Dec 11;503:185-196. Epub 2020 Dec 11.

Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, 630117, Russia; Vall D'Hebron Institut de Recerca, 08035, Barcelona, Spain. Electronic address:

Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.
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http://dx.doi.org/10.1016/j.canlet.2020.12.010DOI Listing
December 2020

Hepatic Lipidomics and Molecular Imaging in a Murine Non-Alcoholic Fatty Liver Disease Model: Insights into Molecular Mechanisms.

Biomolecules 2020 09 3;10(9). Epub 2020 Sep 3.

Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, "Sant Joan" University Hospital, Universitat Rovira i Virgili, Institut de Investigació Sanitaria Pere Virgili (IISPV), 43204 Reus, Spain.

An imbalance between hepatic fatty acid uptake and removal results in ectopic fat accumulation, which leads to non-alcoholic fatty liver disease (NAFLD). The amount and type of accumulated triglycerides seem to play roles in NAFLD progression; however, a complete understanding of how triglycerides contribute to NAFLD evolution is lacking. Our aim was to evaluate triglyceride accumulation in NAFLD in a murine model and its associations with molecular mechanisms involved in liver damage and adipose tissue-liver cross talk by employing lipidomic and molecular imaging techniques. C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were used as a NAFLD model. Standard-diet (STD)-fed animals were used as controls. Standard liver pathology was assessed using conventional techniques. The liver lipidome was analyzed by liquid chromatography-mass spectrometry (LC-MS) and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging. Liver triglycerides were identified by MS/MS. The transcriptome of genes involved in intracellular lipid metabolism and inflammation was assessed by RT-PCR. Plasma leptin, resistin, adiponectin, and FABP4 levels were determined using commercial kits. HFD-fed mice displayed increased liver lipid content. LC-MS analyses identified 14 triglyceride types that were upregulated in livers from HFD-fed animals. Among these 14 types, 10 were identified in liver cross sections by LDI-MS tissue imaging. The accumulation of these triglycerides was associated with the upregulation of lipogenesis and inflammatory genes and the downregulation of β-oxidation genes. Interestingly, the levels of plasma FABP4, but not of other adipokines, were positively associated with 8 of these triglycerides in HFD-fed mice but not in STD-fed mice. Our findings suggest a putative role of FABP4 in the liver-adipose tissue cross talk in NAFLD.
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http://dx.doi.org/10.3390/biom10091275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563600PMC
September 2020

Plasma Metabolomic Profiling Associates Bicuspid Aortic Valve Disease and Ascending Aortic Dilation with a Decrease in Antioxidant Capacity.

J Clin Med 2020 Jul 13;9(7). Epub 2020 Jul 13.

Grup de Recerca Cardiovascular, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, 43201 Reus, Spain.

Background: The bicuspid aortic valve (BAV) is the most common cardiac congenital disease and is associated with an increased risk of developing ascending aorta dilation; which can have fatal consequences. Currently; no established risk biomarkers exist to facilitate the diagnosis and prognosis of BAV.

Methods: Using an untargeted metabolomic approach; we identified the levels of metabolites in plasma samples and compared them depending on the bicuspid or tricuspid morphology of the aortic valve. Including those patients with ascending aortic dilation and/or aortic stenosis ( = 212), we analyzed the role possibly played by alpha-Tocopherol in BAV disease; considering its association with the pathophysiological characteristics of BAV and biomarkers related to inflammation, oxidative stress and endothelial damage, as well as characteristics related to alpha-Tocopherol functionality and metabolism.

Results: We found that BAV patients; especially those with ascending aortic dilation; presented lower antioxidant capacity; as determined by decreased plasma levels of alpha-Tocopherol; paraoxonase 1 and high-density lipoprotein (HDL), as well as increased levels of C-reactive protein (CRP; a biomarker of inflammation) and endothelial microparticles (EMPs; an endothelial damage biomarker). By applying random forest analyses; we evaluated the significant screening capacity of alpha-Tocopherol; CRP and EMPs to classify patients depending on the morphology of the aortic valve.

Discussion: Our findings support the role of decreased antioxidant capacity; increased inflammation and endothelial damage in the pathogenesis of BAV and the progression of aortic dilation. Moreover; determining the plasma levels of alpha-Tocopherol; CRP and EMPs could improve BAV diagnosis in large populations.
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http://dx.doi.org/10.3390/jcm9072215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408840PMC
July 2020

Activation of glycogenolysis and glycolysis in breast cancer stem cell models.

Biochim Biophys Acta Mol Basis Dis 2020 10 24;1866(10):165886. Epub 2020 Jun 24.

Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, 630117 Novosibirsk, Russia; Vall D'Hebron Institut de Recerca, 08035 Barcelona, Spain.. Electronic address:

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http://dx.doi.org/10.1016/j.bbadis.2020.165886DOI Listing
October 2020

Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage.

EMBO J 2020 Jul 2;39(13):e103838. Epub 2020 Jun 2.

Laboratory of Cancer Metabolism, ONCOBELL Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Spain.

Many oncogenes enhance nucleotide usage to increase ribosome content, DNA replication, and cell proliferation, but in parallel trigger p53 activation. Both the impaired ribosome biogenesis checkpoint (IRBC) and the DNA damage response (DDR) have been implicated in p53 activation following nucleotide depletion. However, it is difficult to reconcile the two checkpoints operating together, as the IRBC induces p21-mediated G1 arrest, whereas the DDR requires that cells enter S phase. Gradual inhibition of inosine monophosphate dehydrogenase (IMPDH), an enzyme required for de novo GMP synthesis, reveals a hierarchical organization of these two checkpoints. We find that the IRBC is the primary nucleotide sensor, but increased IMPDH inhibition leads to p21 degradation, compromising IRBC-mediated G1 arrest and allowing S phase entry and DDR activation. Disruption of the IRBC alone is sufficient to elicit the DDR, which is strongly enhanced by IMPDH inhibition, suggesting that the IRBC acts as a barrier against genomic instability.
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http://dx.doi.org/10.15252/embj.2019103838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327477PMC
July 2020

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors.

EMBO Mol Med 2020 06 13;12(6):e11217. Epub 2020 May 13.

Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català d'Oncologia, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.
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http://dx.doi.org/10.15252/emmm.201911217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278557PMC
June 2020

Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions.

Elife 2020 04 7;9. Epub 2020 Apr 7.

Department of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, Spain.

We report the in vivo regulation of Inosine-5´-monophosphate dehydrogenase 1 (IMPDH1) in the retina. IMPDH1 catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, impacting the cellular pools of GMP, GDP and GTP. Guanine nucleotide homeostasis is central to photoreceptor cells, where cGMP is the signal transducing molecule in the light response. Mutations in IMPDH1 lead to inherited blindness. We unveil a light-dependent phosphorylation of retinal IMPDH1 at Thr/Ser in the Bateman domain that desensitizes the enzyme to allosteric inhibition by GDP/GTP. When exposed to bright light, living mice increase the rate of GTP and ATP synthesis in their retinas; concomitant with IMPDH1 aggregate formation at the outer segment layer. Inhibiting IMPDH activity in living mice delays rod mass recovery. We unveil a novel mechanism of regulation of IMPDH1 in vivo, important for understanding GTP homeostasis in the retina and the pathogenesis of adRP10 IMPDH1 mutations.
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http://dx.doi.org/10.7554/eLife.56418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176436PMC
April 2020

rMSIproc: an R package for mass spectrometry imaging data processing.

Bioinformatics 2020 06;36(11):3618-3619

Department of Electronic Engineering, Rovira i Virgili University, IISPV, Tarragona, Spain.

Summary: Mass spectrometry imaging (MSI) can reveal biochemical information directly from a tissue section. MSI generates a large quantity of complex spectral data which is still challenging to translate into relevant biochemical information. Here, we present rMSIproc, an open-source R package that implements a full data processing workflow for MSI experiments performed using TOF or FT-based mass spectrometers. The package provides a novel strategy for spectral alignment and recalibration, which allows to process multiple datasets simultaneously. This enables to perform a confident statistical analysis with multiple datasets from one or several experiments. rMSIproc is designed to work with files larger than the computer memory capacity and the algorithms are implemented using a multi-threading strategy. rMSIproc is a powerful tool able to take full advantage of modern computer systems to completely develop the whole MSI potential.

Availability And Implementation: rMSIproc is freely available at https://github.com/prafols/rMSIproc.

Contact: pere.rafols@urv.cat.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa142DOI Listing
June 2020

Environmental arginine controls multinuclear giant cell metabolism and formation.

Nat Commun 2020 01 22;11(1):431. Epub 2020 Jan 22.

Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, 1090, Vienna, Austria.

Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.
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http://dx.doi.org/10.1038/s41467-020-14285-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976629PMC
January 2020

Essentiality of fatty acid synthase in the 2D to anchorage-independent growth transition in transforming cells.

Nat Commun 2019 11 1;10(1):5011. Epub 2019 Nov 1.

Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Madrid, Spain.

Upregulation of fatty acid synthase (FASN) is a common event in cancer, although its mechanistic and potential therapeutic roles are not completely understood. In this study, we establish a key role of FASN during transformation. FASN is required for eliciting the anaplerotic shift of the Krebs cycle observed in cancer cells. However, its main role is to consume acetyl-CoA, which unlocks isocitrate dehydrogenase (IDH)-dependent reductive carboxylation, producing the reductive power necessary to quench reactive oxygen species (ROS) originated during the switch from two-dimensional (2D) to three-dimensional (3D) growth (a necessary hallmark of cancer). Upregulation of FASN elicits the 2D-to-3D switch; however, FASN's synthetic product palmitate is dispensable for this process since cells satisfy their fatty acid requirements from the media. In vivo, genetic deletion or pharmacologic inhibition of FASN before oncogenic activation prevents tumor development and invasive growth. These results render FASN as a potential target for cancer prevention studies.
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http://dx.doi.org/10.1038/s41467-019-13028-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825217PMC
November 2019

CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression.

Sci Rep 2019 10 1;9(1):14065. Epub 2019 Oct 1.

Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.

CD98 heavy chain (CD98hc) forms heteromeric amino acid (AA) transporters by interacting with different light chains. Cancer cells overexpress CD98hc-transporters in order to meet their increased nutritional and antioxidant demands, since they provide branched-chain AA (BCAA) and aromatic AA (AAA) availability while protecting cells from oxidative stress. Here we show that BCAA and AAA shortage phenocopies the inhibition of mTORC1 signalling, protein synthesis and cell proliferation caused by CD98hc ablation. Furthermore, our data indicate that CD98hc sustains glucose uptake and glycolysis, and, as a consequence, the pentose phosphate pathway (PPP). Thus, loss of CD98hc triggers a dramatic reduction in the nucleotide pool, which leads to replicative stress in these cells, as evidenced by the enhanced DNA Damage Response (DDR), S-phase delay and diminished rate of mitosis, all recovered by nucleoside supplementation. In addition, proper BCAA and AAA availability sustains the expression of the enzyme ribonucleotide reductase. In this regard, BCAA and AAA shortage results in decreased content of deoxynucleotides that triggers replicative stress, also recovered by nucleoside supplementation. On the basis of our findings, we conclude that CD98hc plays a central role in AA and glucose cellular nutrition, redox homeostasis and nucleotide availability, all key for cell proliferation.
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http://dx.doi.org/10.1038/s41598-019-50547-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773781PMC
October 2019

Epigenetic Regulation at the Interplay Between Gut Microbiota and Host Metabolism.

Front Genet 2019 5;10:638. Epub 2019 Jul 5.

Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain.

Gut microbiota communities have coevolved for millions of years in a symbiotic relationship with their mammalian hosts. Elucidating and understanding the molecular mechanisms by which microbiota interacts with its host and how this contributes to the homeostasis of the host is crucial. One of these molecular relationships is the so-called chemical crosstalk between microbiota and host metabolisms, including the poorly explored epigenetic regulation of host tissues by the metabolic activity of gut microbiota in response to changes in diet. DNA methylation and histone modifications are epigenetic marks partly regulated by enzymes such as methylases and acetylases, whose activity depend on host and microbiota metabolites that act as substrates and cofactors for these reactions. However, providing a complete mechanistic description of the regulatory interactions between both metabolisms and the impact on the expression of host genes through an epigenetic modulation, remains elusive. This article presents our perspective on how metabolomic, metagenomic, transcriptomic, and epigenomic data can be used to investigate the "microbiota-nutrient metabolism-epigenetics axis." We also discuss the implications and opportunities this knowledge may have for basic and applied science, such as the impact on the way we structure future research, understand, and prevent diseases like type 2 diabetes or obesity.
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http://dx.doi.org/10.3389/fgene.2019.00638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628876PMC
July 2019

Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans.

Front Physiol 2019 4;10:688. Epub 2019 Jun 4.

Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland.

Cataract, the loss of ocular lens transparency, accounts for ∼50% of worldwide blindness and has been associated with water and solute transport dysfunction across lens cellular barriers. We show that neutral amino acid antiporter LAT2 ) and uniporter TAT1 () are expressed on mouse ciliary epithelium and LAT2 also in lens epithelium. Correspondingly, deletion of LAT2 induced a dramatic decrease in lens essential amino acid levels that was modulated by TAT1 defect. Interestingly, the absence of LAT2 led to increased incidence of cataract in mice, in particular in older females, and a synergistic effect was observed with simultaneous lack of TAT1. Screening in patients diagnosed with congenital or age-related cataract yielded one homozygous single nucleotide deletion segregating in a family with congenital cataract. Expressed in HeLa cells, this LAT2 mutation did not support amino acid uptake. Heterozygous LAT2 variants were also found in patients with cataract some of which showed a reduced transport function when expressed in HeLa cells. Whether heterozygous LAT2 variants may contribute to the pathology of cataract needs to be further investigated. Overall, our results suggest that defects of amino acid transporter LAT2 are implicated in cataract formation, a situation that may be aggravated by TAT1 defects.
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http://dx.doi.org/10.3389/fphys.2019.00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558864PMC
June 2019

Plasma glucose, triglycerides, VLDL, leptin and resistin levels as potential biomarkers for myocardial fat in mice.

Clin Investig Arterioscler 2020 Jan - Feb;32(1):8-14. Epub 2019 Jun 17.

Unidad de Medicina Vascular y Metabolismo, Unitat de Recerca en Lípids i Arteriosclerosis, Hospital Universitario Sant Joan, Universitat Rovira i Virgili, Institut de Investigació Sanitària Pere Virgili, Reus, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Reus, Tarragona, España. Electronic address:

Introduction: The increase in myocardial fat has been proposed as one of the main precursors of myocardial dysfunction due to diabetic aetiology, independently of coronary artery disease. However, biomarkers reflecting the myocardial fat content for the clinical detection of this pathology are currently lacking.

Methods: Correlations between cardiac triglyceride content and plasma levels of major altered molecules during diabetes and cardiac mRNA levels of genes involved in cardiac metabolism (Cd36 and Pdk4) have been explored in a murine model of insulin resistance induced by a high-fat diet.

Results: In insulin-resistant mice, the fatty diet increased myocardial triglyceride levels, compared to control animals fed with a standard diet. The content of cardiac triglycerides was directly associated with plasma levels of glucose, triglycerides, VLDL, resistin and leptin. In addition, an inverse correlation was observed between the content of cardiac triglycerides and the cardiac mRNA levels of Cd36 and Pdk4.

Conclusions: Our data reveal that the cardiac triglyceride content is associated with altered plasma biochemical profile and reprogramming of gene expression aimed to mitigate the impact of ectopic lipid accumulation in the myocardium.
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http://dx.doi.org/10.1016/j.arteri.2019.05.001DOI Listing
November 2020

Fatty acid binding protein 4 (FABP4) as a potential biomarker reflecting myocardial lipid storage in type 2 diabetes.

Metabolism 2019 07 15;96:12-21. Epub 2019 Apr 15.

Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, "Sant Joan" University Hospital, Universitat Rovira i Virgili, Institut de Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, Madrid, Spain. Electronic address:

Objective: Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone involved in the crosstalk between adipose and peripheral tissues, and it contributes to widespread insulin resistance in cells, including cardiac cells. However, the role of this adipokine in regulating cardiac metabolism and myocardial neutral lipid content in patients with type 2 diabetes has not been elucidated.

Methods: The impact of circulating FABP4 on the cardiac neutral lipid content was measured by proton magnetic resonance spectroscopy (H-MRS) in patients with type 2 diabetes. Additionally, circulating FABP4 and the cardiac triglyceride content were analysed in high-fat diet (HFD)-fed mice, and the impact of the exogenous FABP4 was explored in HL-1 cardiac cells.

Results: Serum FABP4 levels were higher in type 2 diabetic patients compared to healthy individuals. Circulating FABP4 levels were associated with myocardial neutral lipid content in type 2 diabetic patients. In HFD-fed mice, both serum FABP4 and myocardial triglyceride content were increased. In FABP4-challenged HL-1 cells, extracellular FABP4 increased intracellular lipid accumulation, which led to impairment of the insulin-signalling pathway and reduced insulin-stimulated glucose uptake. However, these effects were partially reversed by FABP4 inhibition with BMS309403, which attenuated the intracellular lipid content and improved insulin signalling and insulin-stimulated glucose uptake.

Conclusions: Taken together, our results identify FABP4 as a molecule involved in diabetic/lipid-induced cardiomyopathy and indicate that this molecule may be an emerging biomarker for diabetic cardiomyopathy-related disturbances, such as myocardial neutral lipid accumulation. Additionally, FABP4 inhibition may be a potential therapeutic target for metabolic-related cardiac dysfunctions.
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http://dx.doi.org/10.1016/j.metabol.2019.04.007DOI Listing
July 2019

CliqueMS: a computational tool for annotating in-source metabolite ions from LC-MS untargeted metabolomics data based on a coelution similarity network.

Bioinformatics 2019 10;35(20):4089-4097

Department of Chemical Engineering, Universitat Rovira i Virgili, Tarragona, Spain.

Motivation: The analysis of biological samples in untargeted metabolomic studies using LC-MS yields tens of thousands of ion signals. Annotating these features is of the utmost importance for answering questions as fundamental as, e.g. how many metabolites are there in a given sample.

Results: Here, we introduce CliqueMS, a new algorithm for annotating in-source LC-MS1 data. CliqueMS is based on the similarity between coelution profiles and therefore, as opposed to most methods, allows for the annotation of a single spectrum. Furthermore, CliqueMS improves upon the state of the art in several dimensions: (i) it uses a more discriminatory feature similarity metric; (ii) it treats the similarities between features in a transparent way by means of a simple generative model; (iii) it uses a well-grounded maximum likelihood inference approach to group features; (iv) it uses empirical adduct frequencies to identify the parental mass and (v) it deals more flexibly with the identification of the parental mass by proposing and ranking alternative annotations. We validate our approach with simple mixtures of standards and with real complex biological samples. CliqueMS reduces the thousands of features typically obtained in complex samples to hundreds of metabolites, and it is able to correctly annotate more metabolites and adducts from a single spectrum than available tools.

Availability And Implementation: https://CRAN.R-project.org/package=cliqueMS and https://github.com/osenan/cliqueMS.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792096PMC
October 2019

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism.

Mol Cancer Res 2019 07 18;17(7):1531-1544. Epub 2019 Mar 18.

Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth. IMPLICATIONS: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0315DOI Listing
July 2019

Epigenetic loss of the endoplasmic reticulum-associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming.

JCI Insight 2019 03 7;5. Epub 2019 Mar 7.

Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.

The endoplasmic reticulum (ER) of cancer cells needs to adapt to the enhanced proteotoxic stress associated with the accumulation of unfolded, misfolded and transformation-associated proteins. One way by which tumors thrive in the context of ER stress is by promoting ER-Associated Degradation (ERAD), although the mechanisms are poorly understood. Here, we show that the Small p97/VCP Interacting Protein (SVIP), an endogenous inhibitor of ERAD, undergoes DNA hypermethylation-associated silencing in tumorigenesis to achieve this goal. SVIP exhibits tumor suppressor features and its recovery is associated with increased ER stress and growth inhibition. Proteomic and metabolomic analyses show that cancer cells with epigenetic loss of SVIP are depleted in mitochondrial enzymes and oxidative respiration activity. This phenotype is reverted upon SVIP restoration. The dependence of SVIP hypermethylated cancer cells on aerobic glycolysis and glucose was also associated with sensitivity to an inhibitor of the glucose transporter GLUT1. This could be relevant to the management of tumors carrying SVIP epigenetic loss, because these occur in high-risk patients who manifest poor clinical outcomes. Overall, our study provides insights into how epigenetics helps deal with ER stress and how SVIP epigenetic loss in cancer may be amenable to therapies that target glucose transporters.
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http://dx.doi.org/10.1172/jci.insight.125888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538322PMC
March 2019

FELLA: an R package to enrich metabolomics data.

BMC Bioinformatics 2018 Dec 22;19(1):538. Epub 2018 Dec 22.

B2SLab, Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial, Universitat Politècnica de Catalunya, Barcelona, 08028, Spain.

Background: Pathway enrichment techniques are useful for understanding experimental metabolomics data. Their purpose is to give context to the affected metabolites in terms of the prior knowledge contained in metabolic pathways. However, the interpretation of a prioritized pathway list is still challenging, as pathways show overlap and cross talk effects.

Results: We introduce FELLA, an R package to perform a network-based enrichment of a list of affected metabolites. FELLA builds a hierarchical representation of an organism biochemistry from the Kyoto Encyclopedia of Genes and Genomes (KEGG), containing pathways, modules, enzymes, reactions and metabolites. In addition to providing a list of pathways, FELLA reports intermediate entities (modules, enzymes, reactions) that link the input metabolites to them. This sheds light on pathway cross talk and potential enzymes or metabolites as targets for the condition under study. FELLA has been applied to six public datasets -three from Homo sapiens, two from Danio rerio and one from Mus musculus- and has reproduced findings from the original studies and from independent literature.

Conclusions: The R package FELLA offers an innovative enrichment concept starting from a list of metabolites, based on a knowledge graph representation of the KEGG database that focuses on interpretability. Besides reporting a list of pathways, FELLA suggests intermediate entities that are of interest per se. Its usefulness has been shown at several molecular levels on six public datasets, including human and animal models. The user can run the enrichment analysis through a simple interactive graphical interface or programmatically. FELLA is publicly available in Bioconductor under the GPL-3 license.
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http://dx.doi.org/10.1186/s12859-018-2487-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303911PMC
December 2018

Assessing the potential of sputtered gold nanolayers in mass spectrometry imaging for metabolomics applications.

PLoS One 2018 12;13(12):e0208908. Epub 2018 Dec 12.

Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain.

Mass spectrometry imaging (MSI) is a molecular imaging technique that maps the distribution of molecules in biological tissues with high spatial resolution. The most widely used MSI modality is matrix-assisted laser desorption/ionization (MALDI), mainly due to the large variety of analyte classes amenable for MALDI analysis. However, the organic matrices used in classical MALDI may impact the quality of the molecular images due to limited lateral resolution and strong background noise in the low mass range, hindering its use in metabolomics. Here we present a matrix-free laser desorption/ionization (LDI) technique based on the deposition of gold nanolayers on tissue sections by means of sputter-coating. This gold coating method is quick, fully automated, reproducible, and allows growing highly controlled gold nanolayers, necessary for high quality and high resolution MS image acquisition. The performance of the developed method has been tested through the acquisition of MS images of brain tissues. The obtained spectra showed a high number of MS peaks in the low mass region (m/z below 1000 Da) with few background peaks, demonstrating the ability of the sputtered gold nanolayers of promoting the desorption/ionization of a wide range of metabolites. These results, together with the reliable MS spectrum calibration using gold peaks, make the developed method a valuable alternative for MSI applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291137PMC
May 2019

Mind the Gap: Mapping Mass Spectral Databases in Genome-Scale Metabolic Networks Reveals Poorly Covered Areas.

Metabolites 2018 Sep 15;8(3). Epub 2018 Sep 15.

Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Avinguda Paisos Catalans 26, 43007 Tarragona, Spain.

The use of mass spectrometry-based metabolomics to study human, plant and microbial biochemistry and their interactions with the environment largely depends on the ability to annotate metabolite structures by matching mass spectral features of the measured metabolites to curated spectra of reference standards. While reference databases for metabolomics now provide information for hundreds of thousands of compounds, barely 5% of these known small molecules have experimental data from pure standards. Remarkably, it is still unknown how well existing mass spectral libraries cover the biochemical landscape of prokaryotic and eukaryotic organisms. To address this issue, we have investigated the coverage of 38 genome-scale metabolic networks by public and commercial mass spectral databases, and found that on average only 40% of nodes in metabolic networks could be mapped by mass spectral information from standards. Next, we deciphered computationally which parts of the human metabolic network are poorly covered by mass spectral libraries, revealing gaps in the eicosanoids, vitamins and bile acid metabolism. Finally, our network topology analysis based on the betweenness centrality of metabolites revealed the top 20 most important metabolites that, if added to MS databases, may facilitate human metabolome characterization in the future.
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http://dx.doi.org/10.3390/metabo8030051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161000PMC
September 2018

Lifestyle Intervention Decreases Urine Trimethylamine N-Oxide Levels in Prepubertal Children with Obesity.

Obesity (Silver Spring) 2018 10 11;26(10):1603-1610. Epub 2018 Sep 11.

Endocrinology Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.

Objective: Early lifestyle interventions in children with obesity decrease risk of obesity and metabolic disorders during adulthood. This study aimed to identify metabolic signatures associated with lifestyle intervention in urine samples from prepubertal children with obesity.

Methods: Thirty-four prepubertal children with obesity were studied before and after a 6-month lifestyle intervention program, and anthropometric, metabolic, and nutritional variables were collected. A nuclear magnetic resonance approach was applied to obtain the metabolomic profile from urine samples. Partial least squares-discriminant analysis (PLS-DA) was used to achieve group classification and variable importance on projection (VIP) for biomarker selection.

Results: The intervention reduced caloric intake by 10% (P < 0.05) and BMI standard deviation score by 0.47 SD (P < 0.001). PLS-DA identified trimethylamine N-oxide (TMAO, VIP = 2.21) as the metabolite with the highest discrimination properties between groups. Urine TMAO levels were reduced after the intervention (P < 0.05). TMAO is a biomarker of cardiovascular disease risk and is a product of gut microbiota-dependent metabolism of certain dietary compounds, including choline. Notably, changes in TMAO levels after the intervention did not correlate to differences in choline intake but were inversely associated with fiber intake (P < 0.05).

Conclusions: These results indicate that lifestyle intervention decreases TMAO levels in children with obesity.
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http://dx.doi.org/10.1002/oby.22271DOI Listing
October 2018

Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.

FASEB J 2018 May 29:fj201700717RR. Epub 2018 May 29.

Endocrinology Department, Institut de Recerca Sant Joan de Déu, Esplugues, Barcelona, Spain.

Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long-lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long-term programming of metabolic disease. We used a well-characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up-regulation of monoacylglycerol O-acyltransferase ( Mogat) 1 conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1 expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long-lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late-onset insulin resistance and fatty liver disease.-Ramon-Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez-Wienese, R., Vilà, M., Palacios-Marin, I., Fernández-Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez-Chillaron, J. C. Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.
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http://dx.doi.org/10.1096/fj.201700717RRDOI Listing
May 2018

Novel automated workflow for spectral alignment and mass calibration in MS imaging using a sputtered Ag nanolayer.

Anal Chim Acta 2018 Aug 6;1022:61-69. Epub 2018 Apr 6.

Department of Electronic Engineering, Rovira i Virgili University, IISPV, Tarragona, 43007, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, 28029, Spain.

Mass spectrometry imaging (MSI) is a technique that can map analyte spatial distribution directly onto a tissue section. This enables the spatial correlation of molecular entities with a tissue morphology to be investigated. Analyte annotation in MSI is intrinsically linked to the mass accuracy of the data. Mass accuracy and analyte identification are determined by such factors as the experimental set up and the data processing workflow. We present an MSI data processing workflow that uses a label-free approach to compensate for mass shifts. The algorithms developed were designed to perform efficiently even for datasets much larger than computer's memory. Herein, we present the application of the developed processing workflow to a dataset with more than 13.000 pixels and ∼50.000 mass channels. We assessed the overall mass accuracy in the range m/z 400 to 1200 using silver and gold sputtered nanolayers. With our novel processing workflow we were able to obtain mass errors as low as 5 ppm using a TOF instrument.
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http://dx.doi.org/10.1016/j.aca.2018.03.031DOI Listing
August 2018

EXD2 governs germ stem cell homeostasis and lifespan by promoting mitoribosome integrity and translation.

Nat Cell Biol 2018 02 15;20(2):162-174. Epub 2018 Jan 15.

Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Mitochondria are subcellular organelles that are critical for meeting the bioenergetic and biosynthetic needs of the cell. Mitochondrial function relies on genes and RNA species encoded both in the nucleus and mitochondria, and on their coordinated translation, import and respiratory complex assembly. Here, we characterize EXD2 (exonuclease 3'-5' domain-containing 2), a nuclear-encoded gene, and show that it is targeted to the mitochondria and prevents the aberrant association of messenger RNAs with the mitochondrial ribosome. Loss of EXD2 results in defective mitochondrial translation, impaired respiration, reduced ATP production, increased reactive oxygen species and widespread metabolic abnormalities. Depletion of the Drosophila melanogaster EXD2 orthologue (CG6744) causes developmental delays and premature female germline stem cell attrition, reduced fecundity and a dramatic extension of lifespan that is reversed with an antioxidant diet. Our results define a conserved role for EXD2 in mitochondrial translation that influences development and ageing.
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http://dx.doi.org/10.1038/s41556-017-0016-9DOI Listing
February 2018

Metabolomics reveals novel blood plasma biomarkers associated to the BRCA1-mutated phenotype of human breast cancer.

Sci Rep 2017 12 19;7(1):17831. Epub 2017 Dec 19.

Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. del Dr. Josep Laporte, 43204, Reus, Spain.

Hereditary breast and ovarian cancer syndrome (HBOC) is partly due to the presence of mutations in the BRCA genes. Triple-negative (TN) breast cancer (BC) shares histological characteristics with germline BRCA1 mutation-associated tumours. We have investigated the metabolic profiles of human breast cancer (BC) cell lines carrying BRCA1 pathogenic mutations by non-targeted liquid chromatography coupled to mass spectrometry technology. Based on our in vitro results, we performed a targeted metabolomic analysis of plasma samples from TN HBOC patients taking into account their BRCA1 genotype. BRCA1 promoter hypermethylation and the BRCAness phenotype of BC cell lines were also studied. The purpose of this study was to determine the metabolic signature of HBOC syndrome and TNBC patients and to evaluate the potential contribution of the metabolites identified to the genetic diagnosis of breast cancer. The present results show the existence of a differential metabolic signature for BC cells based on the BRCA1 functionality. None of the studied BC cell lines presented hypermethylation of the BRCA1 promoter region. We provide evidence of the existence of free methylated nucleotides capable of distinguishing plasma samples from HBOC patients as BRCA1-mutated and BRCA1 non-mutated, suggesting that they might be considered as BRCA1-like biomarkers for TNBC and HBOC syndrome.
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http://dx.doi.org/10.1038/s41598-017-17897-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736621PMC
December 2017

Null diffusion-based enrichment for metabolomics data.

PLoS One 2017 6;12(12):e0189012. Epub 2017 Dec 6.

Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial, Universitat Politècnica de Catalunya, Barcelona, Spain.

Metabolomics experiments identify metabolites whose abundance varies as the conditions under study change. Pathway enrichment tools help in the identification of key metabolic processes and in building a plausible biological explanation for these variations. Although several methods are available for pathway enrichment using experimental evidence, metabolomics does not yet have a comprehensive overview in a network layout at multiple molecular levels. We propose a novel pathway enrichment procedure for analysing summary metabolomics data based on sub-network analysis in a graph representation of a reference database. Relevant entries are extracted from the database according to statistical measures over a null diffusive process that accounts for network topology and pathway crosstalk. Entries are reported as a sub-pathway network, including not only pathways, but also modules, enzymes, reactions and possibly other compound candidates for further analyses. This provides a richer biological context, suitable for generating new study hypotheses and potential enzymatic targets. Using this method, we report results from cells depleted for an uncharacterised mitochondrial gene using GC and LC-MS data and employing KEGG as a knowledge base. Partial validation is provided with NMR-based tracking of 13C glucose labelling of these cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189012PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718512PMC
December 2017

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD consumption.

Nat Struct Mol Biol 2017 11 9;24(11):902-910. Epub 2017 Oct 9.

Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain.

Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD consumption. The resultant accumulation of the NAD precursor NMN allows for maintenance of mitochondrial NAD pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD consumption and establishing a buffer of NAD precursors in differentiated cells.
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http://dx.doi.org/10.1038/nsmb.3481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791885PMC
November 2017