Prehatch Intestinal Maturation of Turkey Embryos Demonstrated Through Gene Expression Patterns
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The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’S Disease
life Article The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease Dora Csaban 1, Klara Pentelenyi 1, Renata Toth-Bencsik 1, Anett Illes 2, Zoltan Grosz 1, Andras Gezsi 3 and Maria Judit Molnar 1,* 1 Institute of Genomic Medicine and Rare Disorders, Semmelweis University, H-1082 Budapest, Hungary; [email protected] (D.C.); pentelenyi.klara@ med.semmelweis-univ.hu (K.P.); [email protected] (R.T.-B.); [email protected] (Z.G.) 2 PentaCore Laboratory Budapest, H-1094 Budapest, Hungary; [email protected] 3 Department of Measurement and Information Systems, Budapest University of Technology and Economics, H-1117 Budapest, Hungary; [email protected] * Correspondence: [email protected] Abstract: There is increasing evidence that several mitochondrial abnormalities are present in the brains of patients with Alzheimer’s disease (AD). Decreased alpha-ketoglutarate dehydrogenase complex (αKGDHc) activity was identified in some patients with AD. The αKGDHc is a key enzyme in the Krebs cycle. This enzyme is very sensitive to the harmful effect of reactive oxygen species, which gives them a critical role in the Alzheimer and mitochondrial disease research area. Previously, several genetic risk factors were described in association with AD. Our aim was to analyze the associations of rare damaging variants in the genes encoding αKGDHc subunits and AD. The three genes (OGDH, DLST, DLD) encoding αKGDHc subunits were sequenced from different brain regions Citation: Csaban, D.; Pentelenyi, K.; of 11 patients with histologically confirmed AD and the blood of further 35 AD patients. -
Unstructured Regions of Large Enzymatic Complexes Control The
Skalidis et al. Cell Communication and Signaling (2020) 18:136 https://doi.org/10.1186/s12964-020-00631-9 REVIEW Open Access Unstructured regions of large enzymatic complexes control the availability of metabolites with signaling functions Ioannis Skalidis1,2 , Christian Tüting1,2 and Panagiotis L. Kastritis1,2,3* Abstract Metabolites produced via traditional biochemical processes affect intracellular communication, inflammation, and malignancy. Unexpectedly, acetyl-CoA, α-ketoglutarate and palmitic acid, which are chemical species of reactions catalyzed by highly abundant, gigantic enzymatic complexes, dubbed as “metabolons”, have broad “nonmetabolic” signaling functions. Conserved unstructured regions within metabolons determine the yield of these metabolites. Unstructured regions tether functional protein domains, act as spatial constraints to confine constituent enzyme communication, and, in the case of acetyl-CoA production, tend to be regulated by intricate phosphorylation patterns. This review presents the multifaceted roles of these three significant metabolites and describes how their perturbation leads to altered or transformed cellular function. Their dedicated enzymatic systems are then introduced, namely, the pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH) complexes, and the fatty acid synthase (FAS), with a particular focus on their structural characterization and the localization of unstructured regions. Finally, upstream metabolite regulation, in which spatial occupancy of unstructured regions within -
Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma
Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma Alexandre Buffet, Juan Zhang, Heggert Rebel, Eleonora Corssmit, Jeroen Jansen, Erik Hensen, Judith Bovée, Aurélien Morini, Anne-Paule Gimenez-Roqueplo, Frederik Hes, et al. To cite this version: Alexandre Buffet, Juan Zhang, Heggert Rebel, Eleonora Corssmit, Jeroen Jansen, et al.. Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma. The Journal of Clinical Endocrinology & Metabolism, 2020, 10.1210/clinem/dgaa819. hal-03111589 HAL Id: hal-03111589 https://hal.archives-ouvertes.fr/hal-03111589 Submitted on 25 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. XX, No. XX, 1–13 doi:10.1210/clinem/dgaa819 Clinical Research Article Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgaa819/5979643 by Centre de Doc Medico Pharmaceutique user on 08 January 2021 Clinical Research Article Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma Alexandre Buffet,*1,2 Juan Zhang,*3 Heggert Rebel,3 Eleonora P. M. Corssmit,4 Jeroen C. Jansen,5 Erik F. Hensen,5 Judith V. M. G. Bovée,6 Aurélien Morini,7 Anne-Paule Gimenez-Roqueplo,1,2 Frederik J. -
Oxoglutarate Dehydrogenase Multienzyme Complexes Reconstituted from Recombinant
*RevisedView metadata, Manuscript citation and (text similar UNmarked) papers at core.ac.uk brought to you by CORE Click here to view linked References provided by Repository of the Academy's Library Formation of reactive oxygen species by human and bacterial pyruvate and 2- oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components Attila Ambrusa, Natalia S. Nemeriab, Beata Torocsika, Laszlo Trettera, Mattias Nilssona, Frank Jordanb, and Vera Adam-Vizia,* aDepartment of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, Budapest, 1094, Hungary bDepartment of Chemistry, Rutgers, the State University, Newark, NJ 07102, USA *To whom correspondence should be addressed at: Department of Medical Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary. Tel.: +361 266 2773, Fax.: +361 267 0031, E-mail: [email protected] 1 Abstract Individual recombinant components of pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes (PDHc, OGDHc) of human and Escherichia coli (E. coli) origin were expressed and purified from E. coli with optimized protocols. The four multienzyme complexes were each reconstituted under optimal conditions at different stoichiometric ratios. Binding stoichiometries for the highest catalytic efficiency were determined from the rate of NADH generation by the complexes at physiological pH. Since some of these complexes were shown to possess ‘moonlighting’ activities under pathological conditions often accompanied by acidosis, activities were also determined at pH 6.3. As reactive oxygen species (ROS) generation by the E3 component of hOGDHc is a pathologically relevant feature, superoxide generation by the complexes with optimal stoichiometry was measured by the acetylated cytochrome c reduction method in both the forward and the reverse catalytic directions. -
Mitochondrial Fatty Acid Synthesis Coordinates Oxidative Metabolism In
RESEARCH ARTICLE Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria Sara M Nowinski1, Ashley Solmonson2, Scott F Rusin3, J Alan Maschek4,5,6, Claire L Bensard1, Sarah Fogarty1,7, Mi-Young Jeong1, Sandra Lettlova1, Jordan A Berg1, Jeffrey T Morgan1,7, Yeyun Ouyang1, Bradley C Naylor6, Joao A Paulo3, Katsuhiko Funai4, James E Cox1,4,6, Steven P Gygi3, Dennis R Winge1,4,8, Ralph J DeBerardinis2,7, Jared Rutter1,4,7* 1Department of Biochemistry, Salt Lake City, United States; 2Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States; 3Department of Cell Biology, Harvard University School of Medicine, Boston, United States; 4Diabetes & Metabolism Research Center, Salt Lake City, United States; 5Department of Nutrition and Integrative Physiology, Salt Lake City, United States; 6Metabolomics, Proteomics and Mass Spectrometry Core Research Facilities University of Utah, Salt Lake City, United States; 7Howard Hughes Medical Institute, Salt Lake City, United States; 8Department of Internal Medicine, Salt Lake City, United States Abstract Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS mutant mouse skeletal myoblast cell lines display a severe loss of electron transport chain (ETC) complexes and exhibit compensatory metabolic activities including reductive carboxylation. This effect on ETC *For correspondence: complexes appears to be independent of protein lipoylation, the best characterized function of [email protected] mtFAS, as mutants lacking lipoylation have an intact ETC. -
Loss of SDHB Reprograms Energy Metabolisms and Inhibits High Fat Diet
bioRxiv preprint doi: https://doi.org/10.1101/259226; this version posted February 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Loss of SDHB reprograms energy metabolisms and inhibits high fat diet induced metabolic syndromes Chenglong Mu1, Biao Ma1, Chuanmei Zhang1, Guangfeng Geng1, Xinling Zhang1, Linbo Chen1, Meng Wang1, Jie Li1, Tian Zhao1, Hongcheng Cheng1, Qianping Zhang1, Kaili Ma1, Qian Luo1, Rui Chang1, Qiangqiang Liu1, Hao Wu2, Lei Liu2, Xiaohui Wang2, Jun Wang2, Yong Zhang3, Yungang Zhao3, Li Wen3, Quan Chen1,2*, Yushan Zhu1* 1State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China. 2State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. 3Tianjin Key Laboratory of Exercise and Physiology and Sports Medicine, Tianjin University of Sport, Tianjin 300381, China. *Correspondence: [email protected] (QC), [email protected] (YZ) Running title: Complex II regulates energy metabolism (38) 1 bioRxiv preprint doi: https://doi.org/10.1101/259226; this version posted February 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Mitochondrial respiratory complex II utilizes succinate, key substrate of the Krebs cycle, for oxidative phosphorylation, which is essential for glucose metabolism. -
Synthetic Analogues of 2-Oxo Acids Discriminate Metabolic Contribution of the 2-Oxoglutarate and 2-Oxoadipate Dehydrogenases in Mammalian Cells and Tissues Artem V
www.nature.com/scientificreports OPEN Synthetic analogues of 2-oxo acids discriminate metabolic contribution of the 2-oxoglutarate and 2-oxoadipate dehydrogenases in mammalian cells and tissues Artem V. Artiukhov1,2, Aneta Grabarska3, Ewelina Gumbarewicz3, Vasily A. Aleshin1,2, Thilo Kähne4, Toshihiro Obata5,7, Alexey V. Kazantsev6, Nikolay V. Lukashev6, Andrzej Stepulak3, Alisdair R. Fernie5 & Victoria I. Bunik1,2* The biological signifcance of the DHTKD1-encoded 2-oxoadipate dehydrogenase (OADH) remains obscure due to its catalytic redundancy with the ubiquitous OGDH-encoded 2-oxoglutarate dehydrogenase (OGDH). In this work, metabolic contributions of OADH and OGDH are discriminated by exposure of cells/tissues with diferent DHTKD1 expression to the synthesized phosphonate analogues of homologous 2-oxodicarboxylates. The saccharopine pathway intermediates and phosphorylated sugars are abundant when cellular expressions of DHTKD1 and OGDH are comparable, while nicotinate and non-phosphorylated sugars are when DHTKD1 expression is order(s) of magnitude lower than that of OGDH. Using succinyl, glutaryl and adipoyl phosphonates on the enzyme preparations from tissues with varied DHTKD1 expression reveals the contributions of OADH and OGDH to oxidation of 2-oxoadipate and 2-oxoglutarate in vitro. In the phosphonates-treated cells with the high and low DHTKD1 expression, adipate or glutarate, correspondingly, are the most afected metabolites. The marker of fatty acid β-oxidation, adipate, is mostly decreased by the shorter, OGDH-preferring, phosphonate, in agreement with the known OGDH dependence of β-oxidation. The longest, OADH- preferring, phosphonate mostly afects the glutarate level. Coupled decreases in sugars and nicotinate upon the OADH inhibition link the perturbation in glucose homeostasis, known in OADH mutants, to the nicotinate-dependent NAD metabolism. -
1 Novel Expression Signatures Identified by Transcriptional Analysis
ARD Online First, published on October 7, 2009 as 10.1136/ard.2009.108043 Ann Rheum Dis: first published as 10.1136/ard.2009.108043 on 7 October 2009. Downloaded from Novel expression signatures identified by transcriptional analysis of separated leukocyte subsets in SLE and vasculitis 1Paul A Lyons, 1Eoin F McKinney, 1Tim F Rayner, 1Alexander Hatton, 1Hayley B Woffendin, 1Maria Koukoulaki, 2Thomas C Freeman, 1David RW Jayne, 1Afzal N Chaudhry, and 1Kenneth GC Smith. 1Cambridge Institute for Medical Research and Department of Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK 2Roslin Institute, University of Edinburgh, Roslin, Midlothian, EH25 9PS, UK Correspondence should be addressed to Dr Paul Lyons or Prof Kenneth Smith, Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK. Telephone: +44 1223 762642, Fax: +44 1223 762640, E-mail: [email protected] or [email protected] Key words: Gene expression, autoimmune disease, SLE, vasculitis Word count: 2,906 The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Annals of the Rheumatic Diseases and any other BMJPGL products to exploit all subsidiary rights, as set out in their licence (http://ard.bmj.com/ifora/licence.pdf). http://ard.bmj.com/ on September 29, 2021 by guest. Protected copyright. 1 Copyright Article author (or their employer) 2009. -
Proteomic Analysis of Aged Microglia
Flowers et al. Journal of Neuroinflammation (2017) 14:96 DOI 10.1186/s12974-017-0840-7 RESEARCH Open Access Proteomic analysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response Antwoine Flowers1,2, Harris Bell-Temin3, Ahmad Jalloh1,2, Stanley M. Stevens Jr.3 and Paula C. Bickford1,2,4* Abstract Background: Age is the primary risk factor for many diseases. As such, age is a critical co-factor for examination in order to understand the progression and potential intervention in disease progression. Studies examining both the phenotype and transcriptome of aged microglia demonstrated a propensity for the development of a pro-inflammatory phenotype. Less well studied is the concomitant blunting of anti-inflammatory aspects of microglial function with age which also impact plasticity and repair in the CNS. Methods: This study utilizes mass spectrometry-based proteomics to compare primary microglia from young andagedanimals. Results: This study revealed alterations in three clusters of inter-related proteins. The three pathways were inflammatory signaling, mitochondrial function, and cellular metabolism. Analysis of these clusters identified the protein rapamycin-insensitive companion of mTOR (RICTOR), a component of the mTORC2 complex, as a novel upstream regulator of several biological functions that are altered with age and potentially linked to phenotype development. A decrease in mTORC2-dependent AKT S473 phosphorylation, as assessed by insulin growth factor (IGF) treatment, was observed in aged microglia. This novel finding was confirmed by genetic manipulation of the microglial cell line. BV2 cells with diminished RICTOR displayed a phenotype that was strikingly similar to that of aged microglia. This finding is particularly relevant as the mTOR pathway already has a number of pharmacological modulators used clinically. -
Crystal Structure and Interaction Studies of Human DHTKD1 Provide Insight Into a Mitochondrial Megacomplex in Lysine Catabolism
IUCrJ (2020). 7, doi:10.1107/S205225252000696X Supporting information IUCrJ Volume 7 (2020) Supporting information for article: Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism Gustavo A. Bezerra, William R. Foster, Henry J. Bailey, Kevin G. Hicks, Sven W. Sauer, Bianca Dimitrov, Thomas J. McCorvie, Juergen G. Okun, Jared Rutter, Stefan Koelker and Wyatt W. Yue IUCrJ (2020). 7, doi:10.1107/S205225252000696X Supporting information, sup-1 Table S1 Cryo-EM data collection and 3D reconstruction DLST PDB EMD-11014 Data Collection Microscope Glacios Voltage (keV) 200 Nominal Magnification 150,000 x Total electron exposure (e/Å^2) 32.52 Camera Falcon3 Fractions 19 Exposure (sec) 1 Pixel size (Å) 0.96 Nominal defocus range (μm) -1 to -3.1 Micrographs collected (no.) 619 Final refined particles (no.) 3356 Reconstruction Symmetry imposed O Resolution (Å) (global) FSC 4.7 Applied B-factor (Å^2) -281 Model refinement statistics Refmac5 FSC average (%) 73 Rms angle 1.41 Rms bond 0.0056 Rms chiral 0.0858 Model vs Map at FSC 0.5 (Å) 6.5 Model vs Map FSC average > 81 IUCrJ (2020). 7, doi:10.1107/S205225252000696X Supporting information, sup-2 Figure S1 The N-terminus of human DHTKD1. (a) Secondary structure and intrinsic disorder prediction for the human DHTKD1 N-terminal 88 aa, from 9 different servers (H, helices; E, strand, D, disordered). The putative mitochondrial target sequence is bracketed (red). We have expressed DHTKD1 constructs that begin at residues 1, 23 or 45 (arrows). (b) Sequence-based alignment of the N-terminus from human DHTKD1, OGDH, OGDHL and E. -
Supplemental Figures 04 12 2017
Jung et al. 1 SUPPLEMENTAL FIGURES 2 3 Supplemental Figure 1. Clinical relevance of natural product methyltransferases (NPMTs) in brain disorders. (A) 4 Table summarizing characteristics of 11 NPMTs using data derived from the TCGA GBM and Rembrandt datasets for 5 relative expression levels and survival. In addition, published studies of the 11 NPMTs are summarized. (B) The 1 Jung et al. 6 expression levels of 10 NPMTs in glioblastoma versus non‐tumor brain are displayed in a heatmap, ranked by 7 significance and expression levels. *, p<0.05; **, p<0.01; ***, p<0.001. 8 2 Jung et al. 9 10 Supplemental Figure 2. Anatomical distribution of methyltransferase and metabolic signatures within 11 glioblastomas. The Ivy GAP dataset was downloaded and interrogated by histological structure for NNMT, NAMPT, 12 DNMT mRNA expression and selected gene expression signatures. The results are displayed on a heatmap. The 13 sample size of each histological region as indicated on the figure. 14 3 Jung et al. 15 16 Supplemental Figure 3. Altered expression of nicotinamide and nicotinate metabolism‐related enzymes in 17 glioblastoma. (A) Heatmap (fold change of expression) of whole 25 enzymes in the KEGG nicotinate and 18 nicotinamide metabolism gene set were analyzed in indicated glioblastoma expression datasets with Oncomine. 4 Jung et al. 19 Color bar intensity indicates percentile of fold change in glioblastoma relative to normal brain. (B) Nicotinamide and 20 nicotinate and methionine salvage pathways are displayed with the relative expression levels in glioblastoma 21 specimens in the TCGA GBM dataset indicated. 22 5 Jung et al. 23 24 Supplementary Figure 4. -
DHTKD1 and OGDH Display in Vivo Substrate Overlap and Form a Hybrid Ketoacid
bioRxiv preprint doi: https://doi.org/10.1101/645689; this version posted May 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. DHTKD1 and OGDH display in vivo substrate overlap and form a hybrid ketoacid dehydrogenase complex João Leandro1,2, Tetyana Dodatko1,2, Jan Aten3, Ronald C. Hendrickson4, Roberto Sanchez5,6, Chunli Yu1,7, Robert J. DeVita5,6, Sander M. Houten1,2,8,* 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 2Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 3Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands 4Microchemistry and Proteomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 5Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 6Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 7Mount Sinai Genomics, Inc, New York, NY 10029, USA 8Lead Contact *Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/645689; this version posted May 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SUMMARY Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA.