SDHA Gene Succinate Dehydrogenase Complex Flavoprotein Subunit A
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Heme Oxygenase-1 Regulates Mitochondrial Quality Control in the Heart
RESEARCH ARTICLE Heme oxygenase-1 regulates mitochondrial quality control in the heart Travis D. Hull,1,2 Ravindra Boddu,1,3 Lingling Guo,2,3 Cornelia C. Tisher,1,3 Amie M. Traylor,1,3 Bindiya Patel,1,4 Reny Joseph,1,3 Sumanth D. Prabhu,1,4,5 Hagir B. Suliman,6 Claude A. Piantadosi,7 Anupam Agarwal,1,3,5 and James F. George2,3,4 1Department of Medicine, 2Department of Surgery, 3Nephrology Research and Training Center, and 4Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama, USA. 5Department of Veterans Affairs, Birmingham, Alabama, USA. 6Department of Anesthesiology and 7Department of Pulmonary, Allergy and Critical Care, Duke University School of Medicine, Durham, North Carolina, USA. The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. -
Mutations in SDHD Lead to Autosomal Recessive Encephalomyopathy And
Downloaded from http://jmg.bmj.com/ on December 5, 2017 - Published by group.bmj.com Genotype-phenotype correlations ORIGINAL ARTICLE Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency Christopher Benjamin Jackson,1,2 Jean-Marc Nuoffer,3 Dagmar Hahn,3 Holger Prokisch,4,5 Birgit Haberberger,4 Matthias Gautschi,3,6 Annemarie Häberli,3 Sabina Gallati,1 André Schaller1 ▸ Additional material is ABSTRACT succinate to fumarate, is formed by the two larger published online only. To view Background Defects of the mitochondrial respiratory hydrophilic subunits, SDHA and SDHB, which also please visit the journal online (10.1136/jmedgenet-2013- chain complex II (succinate dehydrogenase (SDH) harbour the redox cofactors that participate in elec- 101932) complex) are extremely rare. Of the four nuclear encoded tron transfer to ubiquinone. The cofactor FAD is 1 proteins composing complex II, only mutations in the covalently bound to SDHA which provides the suc- Division of Human Genetics, fl fi Departments of Paediatrics and 70 kDa avoprotein (SDHA) and the recently identi ed cinate binding site, and SDHB possesses three Fe-S Clinical Research, University of complex II assembly factor (SDHAF1) have been found to centres which mediate the electron transfer to ubi- Bern, Bern, Switzerland be causative for mitochondrial respiratory chain diseases. quinone. The smaller hydrophobic SDHC and 2 Graduate School for Cellular Mutations in the other three subunits (SDHB, SDHC, SDHD subunits constitute the membrane anchor and Biomedical Sciences, SDHD) and the second assembly factor (SDHAF2) have and ubiquinone binding sites of CII and localise University of Bern, Bern, 2–4 Switzerland so far only been associated with hereditary CII to the inner mitochondrial membrane. -
Crystal Structure of Bacterial Succinate:Quinone Oxidoreductase Flavoprotein Sdha in Complex with Its Assembly Factor Sdhe
Crystal structure of bacterial succinate:quinone oxidoreductase flavoprotein SdhA in complex with its assembly factor SdhE Megan J. Mahera,1, Anuradha S. Heratha, Saumya R. Udagedaraa, David A. Dougana, and Kaye N. Truscotta,1 aDepartment of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia Edited by Amy C. Rosenzweig, Northwestern University, Evanston, IL, and approved February 14, 2018 (received for review January 4, 2018) Succinate:quinone oxidoreductase (SQR) functions in energy me- quinol:FRD), respectively (13, 15). The importance of this protein tabolism, coupling the tricarboxylic acid cycle and electron transport family, in normal cellular metabolism, is manifested by the iden- chain in bacteria and mitochondria. The biogenesis of flavinylated tification of a mutation in human SDHAF2 (Gly78Arg), which is SdhA, the catalytic subunit of SQR, is assisted by a highly conserved linked to an inherited neuroendocrine disorder, PGL2 (10). Cur- assembly factor termed SdhE in bacteria via an unknown mecha- rently, however, the role of SdhE in flavinylation remains poorly nism. By using X-ray crystallography, we have solved the structure understood. To date, three different modes of action for SdhE/ of Escherichia coli SdhE in complex with SdhA to 2.15-Å resolution. Sdh5 have been proposed, suggesting that SdhE facilitates the Our structure shows that SdhE makes a direct interaction with the binding and delivery of FAD (13), acts as a chaperone for SdhA flavin adenine dinucleotide-linked residue His45 in SdhA and main- (10), or catalyzes the attachment of FAD (10). Moreover, the re- tains the capping domain of SdhA in an “open” conformation. -
Electron Transport Discovery Four Complexes Complex I: Nadhà Coqh2
BI/CH 422/622 OUTLINE: Pyruvate pyruvate dehydrogenase Krebs’ Cycle How did he figure it out? Overview 8 Steps Citrate Synthase Aconitase Isocitrate dehydrogenase Ketoglutarate dehydrogenase Succinyl-CoA synthetase Succinate dehydrogenase Fumarase Malate dehydrogenase Energetics Regulation Summary Oxidative Phosphorylation Energetics (–0.16 V needed for making ATP) Mitochondria Transport (2.4 kcal/mol needed to transport H+ out) Electron transport Discovery Four Complexes Complex I: NADHà CoQH2 Complex II: Succinateà CoQH2 2+ Complex III: CoQH2à Cytochrome C (Fe ) 2+ Complex IV: Cytochrome C (Fe ) à H2O Electron Transport à O2 Inhibitors of Electron Transport Big Drop! • Inhibitors all stop ET and ATP synthesis: very toxic! Spectral work Big Drop! NADH Cyto-a3 Cyto-c1 Big Drop! Cyto-b Cyto-c Cyto-a Fully reduced Flavin Cyto-c + rotenone + antimycin A 300 350 400 450 500 550 600 650 700 1 Electron Transport Electron-Transport Chain Complexes Contain a Series of Electron Carriers • Better techniques for isolating and handling mitochondria, and isolated various fractions of the inner mitochondrial membrane • Measure E°’ • They corresponded to these large drops, and they contained the redox compounds isolated previously. • When assayed for what reactions they could perform, they could perform certain redox reactions and not others. • When isolated, including isolating the individual redox compounds, and measuring the E°’ for each, it was clear that an electron chain was occurring; like a wire! • Lastly, when certain inhibitors were added, some of the redox reactions could be inhibited and others not. Site of the inhibition could be mapped. Electron Transport Electron-Transport Chain Complexes Contain a Series of Electron Carriers • Better techniques for isolating and handling mitochondria, and isolated various fractions of the inner mitochondrial membrane • Measure E°’ • They corresponded to these large drops, and they contained the redox compounds isolated previously. -
Updates on the Genetics of Neuroendocrine Tumors
Updates on the Genetics of Neuroendocrine Tumors NET Patient Conference March 8, 2019 Anna Raper, MS, CGC Division of Translational Medicine and Human Genetics No disclosures 2 3 Overview 1. Cancer/tumor genetics 2. Genetics of neuroendocrine tumors sciencemag.org 4 The Genetics of Cancers and Tumors Hereditary v. Familial v. Sporadic Germline v. somatic genetics Risk When to suspect hereditary susceptibility 5 Cancer Distribution - General Hereditary (5-10%) • Specific gene variant is inherited in family • Associated with increased tumor/cancer risk Familial (10-20%) • Multiple genes and environmental factors may be involved • Some increased tumor/cancer risk Sporadic • Occurs by chance, or related to environmental factors • General population tumor/cancer risk 6 What are genes again? 7 Normal gene Pathogenic gene variant (“mutation”) kintalk.org 8 Cancer is a genetic disease kintalk.org 9 Germline v. Somatic gene mutations 10 Hereditary susceptibility to cancer Germline mutations Depending on the gene, increased risk for certain tumor/cancer types Does not mean an individual WILL develop cancer, but could change screening and management recommendations National Cancer Institute 11 Features that raise suspicion for hereditary condition Specific tumor types Early ages of diagnosis compared to the general population Multiple or bilateral (affecting both sides) tumors Family history • Clustering of certain tumor types • Multiple generations affected • Multiple siblings affected 12 When is genetic testing offered? A hereditary -
Cryoelectron Microscopy Structure and Mechanism of the Membrane-Associated Electron-Bifurcating Flavoprotein Fix/Etfabcx
Cryoelectron microscopy structure and mechanism of the membrane-associated electron-bifurcating flavoprotein Fix/EtfABCX Xiang Fenga, Gerrit J. Schutb, Gina L. Lipscombb, Huilin Lia,1, and Michael W. W. Adamsb,1 aDepartment of Structural Biology, Van Andel Institute, Grand Rapids, MI 49503 and bDepartment of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602 Edited by Michael A. Marletta, University of California, Berkeley, CA, and approved November 22, 2020 (received for review August 10, 2020) The electron-transferring flavoprotein-menaquinone oxidoreduc- FBEB enzymes can be divided into four independently tase ABCX (EtfABCX), also known as FixABCX for its role in evolved groups that are unrelated phylogenetically: 1) electron nitrogen-fixing organisms, is a member of a family of electron- transfer flavoproteins containing EtfAB; 2) [FeFe]-hydrogenases transferring flavoproteins that catalyze electron bifurcation. and formate dehydrogenases containing HydABC; 3) hetero- EtfABCX enables endergonic reduction of ferredoxin (E°′ ∼−450 disulfide reductases containing HdrA; and 4) transhydrogenases mV) using NADH (E°′ −320 mV) as the electron donor by coupling containing NfnAB. X-ray–based structures have been reported this reaction to the exergonic reduction of menaquinone (E°′ −80 for three of the four classes: for butyryl-CoA dehydrogenase mV). Here we report the 2.9 Å structure of EtfABCX, a membrane- (EtfAB-Bcd) (5) and caffeyl-CoA reductase [CarCDE; where associated flavin-based electron bifurcation (FBEB) complex, from CarDE corresponds to EtfAB (6)], for NfnAB (7), and for the a thermophilic bacterium. EtfABCX forms a superdimer with two MvhADG–HdrABC complex (8). No structural information is membrane-associated EtfCs at the dimer interface that contain available for a bifurcating HydABC-type enzyme. -
The Microbiota-Produced N-Formyl Peptide Fmlf Promotes Obesity-Induced Glucose
Page 1 of 230 Diabetes Title: The microbiota-produced N-formyl peptide fMLF promotes obesity-induced glucose intolerance Joshua Wollam1, Matthew Riopel1, Yong-Jiang Xu1,2, Andrew M. F. Johnson1, Jachelle M. Ofrecio1, Wei Ying1, Dalila El Ouarrat1, Luisa S. Chan3, Andrew W. Han3, Nadir A. Mahmood3, Caitlin N. Ryan3, Yun Sok Lee1, Jeramie D. Watrous1,2, Mahendra D. Chordia4, Dongfeng Pan4, Mohit Jain1,2, Jerrold M. Olefsky1 * Affiliations: 1 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA. 2 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. 3 Second Genome, Inc., South San Francisco, California, USA. 4 Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA. * Correspondence to: 858-534-2230, [email protected] Word Count: 4749 Figures: 6 Supplemental Figures: 11 Supplemental Tables: 5 1 Diabetes Publish Ahead of Print, published online April 22, 2019 Diabetes Page 2 of 230 ABSTRACT The composition of the gastrointestinal (GI) microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine (fMLF), are elevated in high fat diet (HFD)- induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon- like peptide-1 (GLP-1). Obese Fpr1-knockout (Fpr1-KO) mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. -
Discovery of Oxidative Enzymes for Food Engineering. Tyrosinase and Sulfhydryl Oxi- Dase
Dissertation VTT PUBLICATIONS 763 1,0 0,5 Activity 0,0 2 4 6 8 10 pH Greta Faccio Discovery of oxidative enzymes for food engineering Tyrosinase and sulfhydryl oxidase VTT PUBLICATIONS 763 Discovery of oxidative enzymes for food engineering Tyrosinase and sulfhydryl oxidase Greta Faccio Faculty of Biological and Environmental Sciences Department of Biosciences – Division of Genetics ACADEMIC DISSERTATION University of Helsinki Helsinki, Finland To be presented for public examination with the permission of the Faculty of Biological and Environmental Sciences of the University of Helsinki in Auditorium XII at the University of Helsinki, Main Building, Fabianinkatu 33, on the 31st of May 2011 at 12 o’clock noon. ISBN 978-951-38-7736-1 (soft back ed.) ISSN 1235-0621 (soft back ed.) ISBN 978-951-38-7737-8 (URL: http://www.vtt.fi/publications/index.jsp) ISSN 1455-0849 (URL: http://www.vtt.fi/publications/index.jsp) Copyright © VTT 2011 JULKAISIJA – UTGIVARE – PUBLISHER VTT, Vuorimiehentie 5, PL 1000, 02044 VTT puh. vaihde 020 722 111, faksi 020 722 4374 VTT, Bergsmansvägen 5, PB 1000, 02044 VTT tel. växel 020 722 111, fax 020 722 4374 VTT Technical Research Centre of Finland, Vuorimiehentie 5, P.O. Box 1000, FI-02044 VTT, Finland phone internat. +358 20 722 111, fax + 358 20 722 4374 Edita Prima Oy, Helsinki 2011 2 Greta Faccio. Discovery of oxidative enzymes for food engineering. Tyrosinase and sulfhydryl oxi- dase. Espoo 2011. VTT Publications 763. 101 p. + app. 67 p. Keywords genome mining, heterologous expression, Trichoderma reesei, Aspergillus oryzae, sulfhydryl oxidase, tyrosinase, catechol oxidase, wheat dough, ascorbic acid Abstract Enzymes offer many advantages in industrial processes, such as high specificity, mild treatment conditions and low energy requirements. -
Function and Structure of Complex Ii of The
Annu. Rev. Biochem. 2003. 72:77–109 doi: 10.1146/annurev.biochem.72.121801.161700 FUNCTION AND STRUCTURE OF COMPLEX II * OF THE RESPIRATORY CHAIN Gary Cecchini Molecular Biology Division, Veterans Administration Medical Center, San Francisco, California 94121, and Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143; email: [email protected] Key Words succinate dehydrogenase, fumarate reductase, quinone oxidoreductase, reactive oxygen species, respiratory chain f Abstract Complex II is the only membrane-bound component of the Krebs cycle and in addition functions as a member of the electron transport chain in mitochondria and in many bacteria. A recent X-ray structural solution of members of the complex II family of proteins has provided important insights into their function. One feature of the complex II structures is a linear electron transport chain that extends from the flavin and iron-sulfur redox cofactors in the membrane extrinsic domain to the quinone and b heme cofactors in the membrane domain. Exciting recent developments in relation to disease in humans and the formation of reactive oxygen species by complex II point to its overall importance in cellular physiology. CONTENTS OVERVIEW OF MEMBRANE-BOUND RESPIRATORY CHAIN .......... 78 COMPLEX II .......................................... 80 OVERALL STRUCTURE OF COMPLEX II ....................... 83 FLAVOPROTEIN SUBUNIT AND FORMATION OF THE COVALENT FAD LINKAGE............................................ 87 CATALYSIS IN COMPLEX II................................ 91 IRON-SULFUR CLUSTERS OF COMPLEX II AND THE ELECTRON TRANS- FER PATHWAY........................................ 94 MEMBRANE DOMAIN OF COMPLEX II ........................ 95 ROLE OF THE b HEME IN COMPLEX II ........................ 99 RELATION OF COMPLEX II TO DISEASE AND REACTIVE OXYGEN SPECIES ............................................100 CONCLUDING REMARKS .................................104 *The U.S. -
Thioredoxin Reductase Two Modes of Catalysis Have Evolved
Eur. J. Biochem. 267, 6110±6117 (2000) q FEBS 2000 MINIREVIEW Thioredoxin reductase Two modes of catalysis have evolved Charles H. Williams Jr1,2, L. David Arscott1, Sylke MuÈ ller2,3, Brett W. Lennon4, Martha L. Ludwig2,4, Pan-Fen Wang2, Donna M. Veine1, Katja Becker5,* and R. Heiner Schirmer5 1Department of Veterans Affairs Medical Center, Ann Arbor, MI, USA; 2Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA; 3Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; 4Biophysics Research Division, University of Michigan, Ann Arbor, MI, USA, 5Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany Thioredoxin reductase (EC 1.6.4.5) is a widely distributed flavoprotein that catalyzes the NADPH-dependent reduction of thioredoxin. Thioredoxin plays several key roles in maintaining the redox environment of the cell. Like all members of the enzyme family that includes lipoamide dehydrogenase, glutathione reductase and mercuric reductase, thioredoxin reductase contains a redox active disulfide adjacent to the flavin ring. Evolution has produced two forms of thioredoxin reductase, a protein in prokaryotes, archaea and lower eukaryotes having a Mr of 35 000, and a protein in higher eukaryotes having a Mr of 55 000. Reducing equivalents are transferred from the apolar flavin binding site to the protein substrate by distinct mechanisms in the two forms of thioredoxin reductase. In the low Mr enzyme, interconversion between two conformations occurs twice in each catalytic cycle. After reduction of the disulfide by the flavin, the pyridine nucleotide domain must rotate with respect to the flavin domain in order to expose the nascent dithiol for reaction with thioredoxin; this motion repositions the pyridine ring adjacent to the flavin ring. -
First-Positive Surveillance Screening in an Asymptomatic SDHA Germline Mutation Carrier
ID: 19-0005 -19-0005 G White and others SDHA surveillance screen ID: 19-0005; May 2019 detected PGL DOI: 10.1530/EDM-19-0005 First-positive surveillance screening in an asymptomatic SDHA germline mutation carrier Correspondence should be addressed Gemma White, Nicola Tufton and Scott A Akker to S A Akker Email Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK [email protected] Summary At least 40% of phaeochromocytomas and paraganglioma’s (PPGLs) are associated with an underlying genetic mutation. The understanding of the genetic landscape of these tumours has rapidly evolved, with 18 associated genes now identified.Amongthese,mutationsinthesubunitsofsuccinatedehydrogenasecomplex(SDH) are the most common, causing around half of familial PPGL cases. Occurrence of PPGLs in carriers of SDHB, SDHC and SDHD subunit mutations has been long reported, but it is only recently that variants in the SDHA subunit have been linked to PPGL formation. Previously documented cases have, to our knowledge, only been found in isolated cases where pathogenic SDHA variants wereidentifiedretrospectively.Wereportthecaseofanasymptomaticsuspectedcarotidbodytumourfoundduring surveillance screening in a 72-year-old female who is a known carrier of a germline SDHA pathogenic variant. To our knowledge,thisisthefirstscreenthatdetectedPPGLfoundinapreviouslyidentifiedSDHA pathogenic variant carrier, duringsurveillanceimaging.Thisfindingsupportstheuseofcascadegenetictestingandsurveillancescreeninginall carriers of a pathogenic SDHA variant. Learning points: •• SDH mutations are important causes of PPGL disease. •• SDHA is much rarer compared to SDHB and SDHD mutations. •• Pathogenicity and penetrance are yet to be fully determined in cases of SDHA-related PPGL. •• Surveillance screening should be used for SDHA PPGL cases to identify recurrence, metastasis or metachronous disease. •• Surveillance screening for SDH-relateddiseaseshouldbeperformedinidentifiedcarriersofapathogenicSDHA variant. -
Fluorescence Spectroscopic Detection of Mitochondrial Flavoprotein Redox
Eur Biophys J (2004) 33: 291–299 DOI 10.1007/s00249-003-0361-4 ARTICLE Andrei Kindzelskii Æ Howard R. Petty Fluorescence spectroscopic detection of mitochondrial flavoprotein redox oscillations and transient reduction of the NADPH oxidase-associated flavoprotein in leukocytes Received: 27 May 2003 / Accepted: 27 September 2003 / Published online: 23 October 2003 Ó EBSA 2003 Abstract Steady-state and time-resolved fluorescence oxidase-associated flavoprotein undergoes a periodic spectroscopy and fluorescence microscopy of leukocyte transient reduction of about 54±2 ms in living cells. flavoproteins have been performed. Both living human This finding is consistent with prior studies indicating peripheral blood monocytes and neutrophils have been that propagating substrate (NADPH) waves periodi- utilized as experimental models, as the former relies cally promote electron transport across the NADPH much more heavily on mitochondrial metabolism for oxidase. energy production than the latter. We confirm previ- ous studies indicating that cellular flavoproteins ab- Keywords Flavoprotein Æ Leukocyte Æ Mitochondria Æ sorb at 460 nm and emit at 530 nm, very similar to NADPH oxidase Æ Fluorescence spectroscopy that of the FAD moiety. Furthermore, the emission properties of intracellular flavoproteins were altered by the metabolic inhibitors rotenone, antimycin A, azide, cyanide, DNP (2,4-dinitrophenol), and FCCP [car- Introduction bonyl cyanide p-(trifluoromethoxy)phenylhydrazone]. Kinetic studies revealed flavoprotein emission oscilla- Electron transport systems play vital roles in energy tions in both monocytes and neutrophils. The flavo- production and in the production of superoxide anions, protein intensity oscillations correlated with the an important reactive oxygen metabolite (ROM). physiological status of the cell and the nature of Flavoproteins participate in (1) mitochondrial electron membrane receptor ligation.