(UCP2) and Uncoupling Protein-3 (UCP3) Expression in Adipose Tissue and Skeletal Muscle in Humans
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Molecular Dynamics Simulations of Mitochondrial Uncoupling Protein 2
International Journal of Molecular Sciences Article Molecular Dynamics Simulations of Mitochondrial Uncoupling Protein 2 Sanja Škulj 1 , Zlatko Brkljaˇca 1, Jürgen Kreiter 2 , Elena E. Pohl 2,* and Mario Vazdar 1,3,* 1 Division of Organic Chemistry and Biochemistry, Ruder¯ Boškovi´cInstitute, Bijeniˇcka54, 10000 Zagreb, Croatia; [email protected] (S.Š.); [email protected] (Z.B.) 2 Department of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, 1210 Vienna, Austria; [email protected] 3 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 16610 Prague, Czech Republic * Correspondence: [email protected] (E.E.P.); [email protected] (M.V.) Abstract: Molecular dynamics (MD) simulations of uncoupling proteins (UCP), a class of transmem- brane proteins relevant for proton transport across inner mitochondrial membranes, represent a complicated task due to the lack of available structural data. In this work, we use a combination of homology modelling and subsequent microsecond molecular dynamics simulations of UCP2 in the DOPC phospholipid bilayer, starting from the structure of the mitochondrial ATP/ADP carrier (ANT) as a template. We show that this protocol leads to a structure that is impermeable to water, in contrast to MD simulations of UCP2 structures based on the experimental NMR structure. We also show that ATP binding in the UCP2 cavity is tight in the homology modelled structure of UCP2 in agreement with experimental observations. Finally, we corroborate our results with conductance measurements in model membranes, which further suggest that the UCP2 structure modeled from ANT protein possesses additional key functional elements, such as a fatty acid-binding site at the R60 Citation: Škulj, S.; Brkljaˇca,Z.; region of the protein, directly related to the proton transport mechanism across inner mitochondrial Kreiter, J.; Pohl, E.E; Vazdar, M. -
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BRIEF COMMUNICATION www.jasn.org Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron Camille Ansermet,* Matthias B. Moor,* Gabriel Centeno,* Muriel Auberson,* † † ‡ Dorothy Zhang Hu, Roland Baron, Svetlana Nikolaeva,* Barbara Haenzi,* | Natalya Katanaeva,* Ivan Gautschi,* Vladimir Katanaev,*§ Samuel Rotman, Robert Koesters,¶ †† Laurent Schild,* Sylvain Pradervand,** Olivier Bonny,* and Dmitri Firsov* BRIEF COMMUNICATION *Department of Pharmacology and Toxicology and **Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland; †Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; ‡Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia; §School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; |Services of Pathology and ††Nephrology, Department of Medicine, University Hospital of Lausanne, Lausanne, Switzerland; and ¶Université Pierre et Marie Curie, Paris, France ABSTRACT Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is crit- leaves.4 Most recently, Legati et al. have ical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the shown an association between genetic kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical polymorphisms in Xpr1 and primary fa- sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the milial brain calcification disorder.5 How- molecular identity of the protein(s) participating in the basolateral Pi efflux remains ever, the role of XPR1 in the maintenance unknown. Evidence has suggested that xenotropic and polytropic retroviral recep- of Pi homeostasis remains unknown. Here, tor 1 (XPR1) might be involved in this process. Here, we show that conditional in- we addressed this issue in mice deficient for activation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi Xpr1 in the nephron. -
Altered Expression and Function of Mitochondrial Я-Oxidation Enzymes
0031-3998/01/5001-0083 PEDIATRIC RESEARCH Vol. 50, No. 1, 2001 Copyright © 2001 International Pediatric Research Foundation, Inc. Printed in U.S.A. Altered Expression and Function of Mitochondrial -Oxidation Enzymes in Juvenile Intrauterine-Growth-Retarded Rat Skeletal Muscle ROBERT H. LANE, DAVID E. KELLEY, VLADIMIR H. RITOV, ANNA E. TSIRKA, AND ELISA M. GRUETZMACHER Department of Pediatrics, UCLA School of Medicine, Mattel Children’s Hospital at UCLA, Los Angeles, California 90095, U.S.A. [R.H.L.]; and Departments of Internal Medicine [D.E.K., V.H.R.] and Pediatrics [R.H.L., A.E.T., E.M.G.], University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, Pennsylvania 15213, U.S.A. ABSTRACT Uteroplacental insufficiency and subsequent intrauterine creased in IUGR skeletal muscle mitochondria, and isocitrate growth retardation (IUGR) affects postnatal metabolism. In ju- dehydrogenase activity was unchanged. Interestingly, skeletal venile rats, IUGR alters skeletal muscle mitochondrial gene muscle triglycerides were significantly increased in IUGR skel- expression and reduces mitochondrial NADϩ/NADH ratios, both etal muscle. We conclude that uteroplacental insufficiency alters of which affect -oxidation flux. We therefore hypothesized that IUGR skeletal muscle mitochondrial lipid metabolism, and we gene expression and function of mitochondrial -oxidation en- speculate that the changes observed in this study play a role in zymes would be altered in juvenile IUGR skeletal muscle. To test the long-term morbidity associated with IUGR. (Pediatr Res 50: this hypothesis, mRNA levels of five key mitochondrial enzymes 83–90, 2001) (carnitine palmitoyltransferase I, trifunctional protein of -oxi- dation, uncoupling protein-3, isocitrate dehydrogenase, and mi- Abbreviations tochondrial malate dehydrogenase) and intramuscular triglycer- CPTI, carnitine palmitoyltransferase I ides were quantified in 21-d-old (preweaning) IUGR and control IUGR, intrauterine growth retardation rat skeletal muscle. -
Mt-Atp8 Gene in the Conplastic Mouse Strain C57BL/6J-Mtfvb/NJ on the Mitochondrial Function and Consequent Alterations to Metabolic and Immunological Phenotypes
From the Lübeck Institute of Experimental Dermatology of the University of Lübeck Director: Prof. Dr. Saleh M. Ibrahim Interplay of mtDNA, metabolism and microbiota in the pathogenesis of AIBD Dissertation for Fulfillment of Requirements for the Doctoral Degree of the University of Lübeck from the Department of Natural Sciences Submitted by Paul Schilf from Rostock Lübeck, 2016 First referee: Prof. Dr. Saleh M. Ibrahim Second referee: Prof. Dr. Stephan Anemüller Chairman: Prof. Dr. Rainer Duden Date of oral examination: 30.03.2017 Approved for printing: Lübeck, 06.04.2017 Ich versichere, dass ich die Dissertation ohne fremde Hilfe angefertigt und keine anderen als die angegebenen Hilfsmittel verwendet habe. Weder vorher noch gleichzeitig habe ich andernorts einen Zulassungsantrag gestellt oder diese Dissertation vorgelegt. ABSTRACT Mitochondria are critical in the regulation of cellular metabolism and influence signaling processes and inflammatory responses. Mitochondrial DNA mutations and mitochondrial dysfunction are known to cause a wide range of pathological conditions and are associated with various immune diseases. The findings in this work describe the effect of a mutation in the mitochondrially encoded mt-Atp8 gene in the conplastic mouse strain C57BL/6J-mtFVB/NJ on the mitochondrial function and consequent alterations to metabolic and immunological phenotypes. This work provides insights into the mutation-induced cellular adaptations that influence the inflammatory milieu and shape pathological processes, in particular focusing on autoimmune bullous diseases, which have recently been reported to be associated with mtDNA polymorphisms in the human MT-ATP8 gene. The mt-Atp8 mutation diminishes the assembly of the ATP synthase complex into multimers and decreases mitochondrial respiration, affects generation of reactive oxygen species thus leading to a shift in the metabolic balance and reduction in the energy state of the cell as indicated by the ratio ATP to ADP. -
The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: a Systematic Review
SYSTEMATIC REVIEW published: 14 June 2021 doi: 10.3389/fgene.2021.675053 The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: A Systematic Review Assefa M. Baye 1, Teferi G. Fanta 1, Moneeza K. Siddiqui 2 and Adem Y. Dawed 2* 1 Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia, 2 Division of Population Health and Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, United Kingdom Background: Adverse drug reactions (ADR) are a major clinical problem accounting for significant hospital admission rates, morbidity, mortality, and health care costs. One-third of people with diabetes experience at least one ADR. However, there is notable interindividual heterogeneity resulting in patient harm and unnecessary medical costs. Genomics is at the forefront of research to understand interindividual variability, and there are many genotype-drug response associations in diabetes with inconsistent findings. Here, we conducted a systematic review to comprehensively examine and synthesize the effect of genetic polymorphisms on the incidence of ADRs of oral glucose-lowering drugs in people with type 2 diabetes. Edited by: Celine Verstuyft, Methods: A literature search was made to identify articles that included specific Université Paris-Saclay, France results of research on genetic polymorphism and adverse effects associated with Reviewed by: oral glucose-lowering drugs. The electronic search was carried out on 3rd October Zhiguo Xie, 2020, through Cochrane Library, PubMed, and Web of Science using keywords and Central South University, China Vera Ribeiro, MeSH terms. University of Algarve, Portugal Result: Eighteen articles consisting of 10, 383 subjects were included in this review. -
The Emerging Neuroprotective Role of Mitochondrial Uncoupling Protein
Review Article • DOI: 10.1515/tnsci-2015-0019 • Translational Neuroscience • 6 • 2015 • 179-186 Translational Neuroscience THE EMERGING NEUROPROTECTIVE ROLE Kieran P. Normoyle1,2,3, OF MITOCHONDRIAL Miri Kim2,4, Arash Farahvar5, UNCOUPLING PROTEIN-2 Daniel Llano1,6,7, Kevin Jackson7,8, IN TRAUMATIC BRAIN INJURY Huan Wang6,8* Abstract 1Department of Molecular and Integrative Traumatic brain injury (TBI) is a multifaceted disease with intrinsically complex heterogeneity and remains a Physiology, University of Illinois at Urbana- Champaign, Urbana, IL, USA significant clinical challenge to manage. TBI model systems have demonstrated many mechanisms that contribute 2College of Medicine, University of Illinois at to brain parenchymal cell death, including glutamate and calcium toxicity, oxidative stress, inflammation, and Urbana-Champaign, Urbana, IL, USA mitochondrial dysfunction. Mitochondria are critically regulated by uncoupling proteins (UCP), which allow 3Department of Child Neurology, Massachusetts protons to leak back into the matrix and thus reduce the mitochondrial membrane potential by dissipating the General Hospital, Boston, MA, USA 4Department of Cell and Developmental Biology, proton motive force. This uncoupling of oxidative phosphorylation from adenosine triphosphate (ATP) synthesis University of Illinois at Urbana-Champaign, is potentially critical for protection against cellular injury as a result of TBI and stroke. A greater understanding Urbana, IL, USA of the underlying mechanism or mechanisms by which uncoupling protein-2 -
Genes Associated with Metabolic Syndrome And
Clinical Case Reports and Reviews Review Article ISSN: 2059-0393 Genes associated with metabolic syndrome and hyperuricemia: An overview Shabnam Pokharel1*, Sanjeev Acharya2 and Abu Taiub Mohammed Mohiuddin Chowdhury3 1Department of Preventive Medicine, Jiamusi University, Heilongjiang Province, China 2Department of Nephrology, 1st Affiliated Hospital of Jiamusi University, Jiamusi city, Heilongjiang province, P. R China 3Department of Digestive Disease, 1st Affiliated Hospital of Jiamusi University, Jiamusi city, Heilongjiang Province, P.R China Abstract Purposes: Recently, different studies have found genetic basis for hyperuricemia, metabolic syndrome and different components of it. The purpose of our review is to overview the different genes that have been studied with regard to hyperuricemia, metabolic syndrome and its components. Method: We made this review by systematically searching relevant literatures using multiple keywords and standardized terminology on PubMed, Nature.com, Hindawi.com, Plosone.com etc and other online resources related to the topic of our study. Findings: Serum uric acid level is influenced by diet, cellular breakdown, renal elimination and correlates with metabolic syndrome, diabetes mellitus, blood pressure, gout, and cardiovascular disease. Metabolic syndrome has strong association with the development of type II diabetes and risk of cardiovascular morbidity and mortality.We found associations of different genes regarding hyperuricemia, metabolic syndrome and its components like diabetes mellitus, obesity, dyslipidemia, and hypertension. Conclusions: This review provides evidence that different genes are responsible for the causation of Metabolic syndrome and its each component. Further genetic studies with different population groups and races in different parts of the world need to be carried out to find specific relation and effect of each gene in each specific component of our study. -
The Pathogenetic Role of Β-Cell Mitochondria in Type 2 Diabetes
236 3 Journal of M Fex et al. Mitochondria in β-cells 236:3 R145–R159 Endocrinology REVIEW The pathogenetic role of β-cell mitochondria in type 2 diabetes Malin Fex1, Lisa M Nicholas1, Neelanjan Vishnu1, Anya Medina1, Vladimir V Sharoyko1, David G Nicholls1, Peter Spégel1,2 and Hindrik Mulder1 1Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden 2Department of Chemistry, Center for Analysis and Synthesis, Lund University, Sweden Correspondence should be addressed to H Mulder: [email protected] Abstract Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic Key Words β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts f TCA cycle of insulin in response to glucose. This results in hyperglycemia and metabolic f coupling signal dysregulation. Evidence has recently been mounting that mitochondrial dysfunction f oxidative phosphorylation plays an important role in these processes. Monogenic dysfunction of mitochondria is a f mitochondrial transcription rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, f genetic variation we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. -
The Role of Uncoupling Protein 3 in Human Physiology
The role of uncoupling protein 3 in human physiology W. Timothy Garvey J Clin Invest. 2003;111(4):438-441. https://doi.org/10.1172/JCI17835. Commentary Obesity is simply understood as an imbalance between energy intake and expenditure in favor of weight accretion. However, the human biological interface between food consumption and energy dissipation results in broad individual differences in eating behavior, physical activity, and efficiency of fuel storage and metabolism. In particular, the basal metabolic rate, which accounts for the greatest portion of overall energy expenditure, can vary almost twofold among individuals. Classically, three major biochemical systems are believed to contribute to basal thermogenesis: futile cycles, Na+/K+ATPase activity, and mitochondrial proton leak. The latter is the most important quantitative contributor and can explain up to 50% of the basal metabolic rate (1). The molecular basis of mitochondrial proton leak is unclear, despite its importance in the understanding of energy balance and its potential as a therapeutic target for obesity treatment. The article by Hesselink and colleagues in this issue of the JCI (2) addresses whether uncoupling protein 3 contributes to mitochondrial proton leak in human skeletal muscle. Mitochondrial respiration and oxidative phosphorylation The oxidation of fatty acids and pyruvate takes place in mitochondria, where energy is converted into ATP for use in cellular processes. Reducing equivalents are extracted from substrates and sequentially passed from electron donors (reductants) to acceptors (oxidants) along the mitochondrial respiratory chain to molecular oxygen. The electron transport system is located on […] Find the latest version: https://jci.me/17835/pdf COMMENTARY See the related article beginning on page 479. -
Cldn19 Clic2 Clmp Cln3
NewbornDx™ Advanced Sequencing Evaluation When time to diagnosis matters, the NewbornDx™ Advanced Sequencing Evaluation from Athena Diagnostics delivers rapid, 5- to 7-day results on a targeted 1,722-genes. A2ML1 ALAD ATM CAV1 CLDN19 CTNS DOCK7 ETFB FOXC2 GLUL HOXC13 JAK3 AAAS ALAS2 ATP1A2 CBL CLIC2 CTRC DOCK8 ETFDH FOXE1 GLYCTK HOXD13 JUP AARS2 ALDH18A1 ATP1A3 CBS CLMP CTSA DOK7 ETHE1 FOXE3 GM2A HPD KANK1 AASS ALDH1A2 ATP2B3 CC2D2A CLN3 CTSD DOLK EVC FOXF1 GMPPA HPGD K ANSL1 ABAT ALDH3A2 ATP5A1 CCDC103 CLN5 CTSK DPAGT1 EVC2 FOXG1 GMPPB HPRT1 KAT6B ABCA12 ALDH4A1 ATP5E CCDC114 CLN6 CUBN DPM1 EXOC4 FOXH1 GNA11 HPSE2 KCNA2 ABCA3 ALDH5A1 ATP6AP2 CCDC151 CLN8 CUL4B DPM2 EXOSC3 FOXI1 GNAI3 HRAS KCNB1 ABCA4 ALDH7A1 ATP6V0A2 CCDC22 CLP1 CUL7 DPM3 EXPH5 FOXL2 GNAO1 HSD17B10 KCND2 ABCB11 ALDOA ATP6V1B1 CCDC39 CLPB CXCR4 DPP6 EYA1 FOXP1 GNAS HSD17B4 KCNE1 ABCB4 ALDOB ATP7A CCDC40 CLPP CYB5R3 DPYD EZH2 FOXP2 GNE HSD3B2 KCNE2 ABCB6 ALG1 ATP8A2 CCDC65 CNNM2 CYC1 DPYS F10 FOXP3 GNMT HSD3B7 KCNH2 ABCB7 ALG11 ATP8B1 CCDC78 CNTN1 CYP11B1 DRC1 F11 FOXRED1 GNPAT HSPD1 KCNH5 ABCC2 ALG12 ATPAF2 CCDC8 CNTNAP1 CYP11B2 DSC2 F13A1 FRAS1 GNPTAB HSPG2 KCNJ10 ABCC8 ALG13 ATR CCDC88C CNTNAP2 CYP17A1 DSG1 F13B FREM1 GNPTG HUWE1 KCNJ11 ABCC9 ALG14 ATRX CCND2 COA5 CYP1B1 DSP F2 FREM2 GNS HYDIN KCNJ13 ABCD3 ALG2 AUH CCNO COG1 CYP24A1 DST F5 FRMD7 GORAB HYLS1 KCNJ2 ABCD4 ALG3 B3GALNT2 CCS COG4 CYP26C1 DSTYK F7 FTCD GP1BA IBA57 KCNJ5 ABHD5 ALG6 B3GAT3 CCT5 COG5 CYP27A1 DTNA F8 FTO GP1BB ICK KCNJ8 ACAD8 ALG8 B3GLCT CD151 COG6 CYP27B1 DUOX2 F9 FUCA1 GP6 ICOS KCNK3 ACAD9 ALG9 -
Perspectives in Diabetes Uncoupling Proteins 2 and 3 Potential Regulators of Mitochondrial Energy Metabolism Olivier Boss, Thilo Hagen, and Bradford B
Perspectives in Diabetes Uncoupling Proteins 2 and 3 Potential Regulators of Mitochondrial Energy Metabolism Olivier Boss, Thilo Hagen, and Bradford B. Lowell Mitochondria use energy derived from fuel combustion fuels and oxygen are converted into carbon dioxide, water, to create a proton electrochemical gradient across the and ATP (Fig. 1). The key challenge for the organism is to reg- mitochondrial inner membrane. This intermediate form ulate these many steps so that rates of ATP production are of energy is then used by ATP synthase to synthesize equal to rates of ATP utilization. This is not a small task given AT P. Uncoupling protein-1 (UCP1) is a brown fat–spe- that rates of ATP utilization can quickly increase severalfold cific mitochondrial inner membrane protein with proton (up to 100-fold in muscle during contraction). transport activity. UCP1 catalyzes a highly regulated proton leak, converting energy stored within the mito- Fuel metabolism and oxidative phosphorylation consist chondrial proton electrochemical potential gradient to of many tightly coupled enzymatic reactions (Fig. 1), which heat. This uncouples fuel oxidation from conversion of are regulated, in part, by ADP availability. Control by ADP is ADP to AT P. In rodents, UCP1 activity and brown fat accounted for by the chemiosmotic hypothesis of Mitchell (1). contribute importantly to whole-body energy expendi- Oxidation of fuels via the electron transport chain generates ture. Recently, two additional mitochondrial carriers a proton electrochemical potential gradient ( µH+) across with high similarity to UCP1 were molecularly cloned. the mitochondrial inner membrane. Protons reenter the In contrast to UCP1, UCP2 is expressed widely, and mitochondrial matrix via ATP synthase (F0F1-A TPase) in a UCP3 is expressed preferentially in skeletal muscle. -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in