Mitochondrial DNA (Mtdna) Test Requisition
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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. -
Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ Ortal Barel,1 Zamir Shorer,2 Hagit Flusser,2 Rivka Ofir,1 Ginat Narkis,1 Gal Finer,1 Hanah Shalev,2 Ahmad Nasasra,2 Ann Saada,3 and Ohad S. Birk1,4,* A consanguineous Israeli Bedouin kindred presented with an autosomal-recessive nonlethal phenotype of severe psychomotor retarda- tion and extrapyramidal signs, dystonia, athetosis and ataxia, mild axial hypotonia, and marked global dementia with defects in verbal and expressive communication skills. Metabolic workup was normal except for mildly elevated blood lactate levels. Brain magnetic resonance imaging (MRI) showed increased density in the putamen, with decreased density and size of the caudate and lentiform nuclei. Reduced activity specifically of mitochondrial complex III and variable decrease in complex I activity were evident in muscle biopsies. Homozygosity of affected individuals to UQCRB and to BCSIL, previously associated with isolated complex III deficiency, was ruled out. Genome-wide linkage analysis identified a homozygosity locus of approximately 9 cM on chromosome 5q31 that was further narrowed down to 2.14 cM, harboring 30 genes (logarithm of the odds [LOD] score 8.82 at q ¼ 0). All 30 genes were sequenced, revealing a single missense (p.Ser45Phe) mutation in UQCRQ (encoding ubiquinol-cytochrome c reductase, complex III subunit VII, 9.5 kDa), one of the ten nuclear -
Biomarkers of Mitotoxicity After Acute Liver Injury: Further Insights Into the Interpretation of Glutamate Dehydrogenase
Journal of Clinical and Translational Research 10.18053/Jctres/07.202101.005 MINI REVIEW Biomarkers of mitotoxicity after acute liver injury: further insights into the interpretation of glutamate dehydrogenase Mitchell R. McGill1,2* and Hartmut Jaeschke3 1. Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, 4301 W. Markham St, Little Rock, AR, USA, 72205 2. Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, USA, 72205 3. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, USA, 66160 *Corresponding author Mitchell R. McGill, PhD Department of Environmental Health Sciences & Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR Tel: +1 501-526-6696 Email: [email protected] Article information: Received: November 03, 2020 Revised: December 09, 2020 Accepted: December 10, 2020 Journal of Clinical and Translational Research 10.18053/Jctres/07.202101.005 ABSTRACT Background: Acetaminophen (APAP) is a popular analgesic, but overdose causes acute liver injury and sometimes death. Decades of research have revealed that mitochondrial damage is central in the mechanisms of toxicity in rodents, but we know much less about the role of mitochondria in humans. Due to the challenge of procuring liver tissue from APAP overdose patients, non-invasive mechanistic biomarkers are necessary to translate the mechanisms of APAP hepatotoxicity from rodents to patients. It was recently proposed that the mitochondrial matrix enzyme glutamate dehydrogenase (GLDH) can be measured in circulation as a biomarker of mitochondrial damage. -
Tyramine and Amyloid Beta 42: a Toxic Synergy
biomedicines Article Tyramine and Amyloid Beta 42: A Toxic Synergy Sudip Dhakal and Ian Macreadie * School of Science, RMIT University, Bundoora, VIC 3083, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-3-9925-6627 Received: 5 May 2020; Accepted: 27 May 2020; Published: 30 May 2020 Abstract: Implicated in various diseases including Parkinson’s disease, Huntington’s disease, migraines, schizophrenia and increased blood pressure, tyramine plays a crucial role as a neurotransmitter in the synaptic cleft by reducing serotonergic and dopaminergic signaling through a trace amine-associated receptor (TAAR1). There appear to be no studies investigating a connection of tyramine to Alzheimer’s disease. This study aimed to examine whether tyramine could be involved in AD pathology by using Saccharomyces cerevisiae expressing Aβ42. S. cerevisiae cells producing native Aβ42 were treated with different concentrations of tyramine, and the production of reactive oxygen species (ROS) was evaluated using flow cytometric cell analysis. There was dose-dependent ROS generation in wild-type yeast cells with tyramine. In yeast producing Aβ42, ROS levels generated were significantly higher than in controls, suggesting a synergistic toxicity of Aβ42 and tyramine. The addition of exogenous reduced glutathione (GSH) was found to rescue the cells with increased ROS, indicating depletion of intracellular GSH due to tyramine and Aβ42. Additionally, tyramine inhibited the respiratory growth of yeast cells producing GFP-Aβ42, while there was no growth inhibition when cells were producing GFP. Tyramine was also demonstrated to cause increased mitochondrial DNA damage, resulting in the formation of petite mutants that lack respiratory function. -
PARL Deficiency in Mouse Causes Complex III Defects, Coenzyme Q Depletion, and Leigh-Like Syndrome
PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome Marco Spinazzia,b,1, Enrico Radaellic, Katrien Horréa,b, Amaia M. Arranza,b, Natalia V. Gounkoa,b,d, Patrizia Agostinise, Teresa Mendes Maiaf,g,h, Francis Impensf,g,h, Vanessa Alexandra Moraisi, Guillermo Lopez-Lluchj,k, Lutgarde Serneelsa,b, Placido Navasj,k, and Bart De Stroopera,b,l,1 aVIB Center for Brain and Disease Research, 3000 Leuven, Belgium; bDepartment of Neurosciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; cComparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6051; dElectron Microscopy Platform, VIB Bio Imaging Core, 3000 Leuven, Belgium; eCell Death Research & Therapy Laboratory, Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; fVIB Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; gVIB Proteomics Core, VIB, 9000 Ghent, Belgium; hDepartment for Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; iInstituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; jCentro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas-Junta de Andalucía, 41013 Seville, Spain; kCentro de Investigaciones Biomédicas en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain; and lUK Dementia Research Institute, University College London, WC1E 6BT London, United Kingdom Edited by Richard D. Palmiter, University of Washington, Seattle, WA, and approved November 21, 2018 (received for review July 11, 2018) The mitochondrial intramembrane rhomboid protease PARL has been proposed that PARL exerts proapoptotic effects via misprocessing implicated in diverse functions in vitro, but its physiological role in of the mitochondrial Diablo homolog (hereafter DIABLO) (10). -
UQCRFS1N Assembles Mitochondrial Respiratory Complex-III Into an Asymmetric 21-Subunit Dimer
Protein Cell 2018, 9(6):586–591 https://doi.org/10.1007/s13238-018-0515-x Protein & Cell LETTER TO THE EDITOR UQCRFS1N assembles mitochondrial respiratory complex-III into an asymmetric 21-subunit dimer Dear Editor, Although several structures have been solved with very high resolution, the full length N-terminal processed peptide (1– Mitochondrial respiratory chain consists of four multimeric 78 amino acids, UQCRFS1N) of the iron-sulfur Rieske pro- protein complexes, Complex I-IV (CI, NADH dehydroge- tein (UQCRFS1) subunit has not been assigned in all of nase; CII, succinate:ubiquinone oxidoreductase; CIII, cyto- these structures (Table 1). UQCRFS1N is the N-terminal chrome bc1 complex; and CIV, cytochrome c oxidase). Cell mitochondrial targeting sequence of UQCRFS1, and after its These four complexes transfer electrons from NADH or cleavage from the precursor, this small peptide remains & FADH to oxygen and pump protons from mitochondrial 2 bound to CIII with unknown functions. In this letter, we show matrix to intermembrane space, generating electrochemical that one UQCRFS1N links the two 10-subunit CIII protomers gradient across the inner membrane which is harnessed by together to form the intact CIII, which resultantly contains complex V to synthesize ATP, providing the majority of only 21 subunits rather than previously assumed 22 subunits energy acquired by living organisms. Respiratory chain Protein (Fig. 1A and 1B). complexes were reported to interact with each other to form Firstly, we rebuilt the high-resolution crystal structures of supercomplexes, even megacomplex (Guo et al., 2017). bovine CIII (PDB: 2A06) (Huang et al., 2005) and chicken However, despite decades of intensive research, many CIII (PDB:3TGU) (Hao et al., 2012). -
Supplementary Information ADC Mar 2017
Supplementary Material for Diagnosing Childhood-onset Inborn Errors of Metabolism by Next Generation Sequencing Clinical Proforma ! CLINICAL&PROFORMA&FOR&MANCHESTER&METABOLIC&NGS&PANELS& ! Patient!Name:!! ! Sex:!Male! !Female! ! ! Date!of!Birth!(D/M/Y):! !! Reference!Number:! !! ! Clinical&Information& ! ! Clinical!features! ! ! ! Age!of!onset! ! ! ! Details!of!relevant!biochemical! ! testing! ! ! Likely!mode!of!inheritance! Dominant! !!!!!XHlinked! !!!!!!Recessive! !!!!!!Sporadic! !!!!!!Information!not!available! ! Parental!consanguinity!H!!!!!!!Yes! !!!!!!!!!!!!!!!!!!!!!No! !!!!!!!!!!!!!!!!!!!Information!not!available! !!!! Relevant!family!history!! ! (draw!brief!pedigrees!if!needed)! ! and!any!other!relevant! !!!!!!!!!!!!!!!!!!!!!!!!!! information! ! Possible!or!likely!diagnosis!or! ! disease!group! ! Is!the!patient!known!to!any! ! Consultants!in!Manchester! ! Genetics!department?! ! (If!yes,!give!name)!! ! & Gene&panel&request& AA!+!NT! ! Key:&&AA!Disorders!of!amino!acid!metabolism!and!cerebral!organic!acid! AMN!+!FAOD!+!KET! ! disorders;!NT!Disorders!of!neurotransmission;!AMN!Disorders!associated! with!hyperammonaemia;!FAOD(Fatty!acid!oxidation!defects;!KET!Disorders! OA!+!VIT! ! of!ketogenesis!or!ketolysis;!OA!Organic!acidaemias,!including!disorders!of! CHO! & branched!chain!amino!acid!catabolism,!3>methylglutaconic!acidurias;!VIT! LSD!+!NCL! & Folate!and!cobalamin!defects,!also!riboflavin!transport!defects,!and!biotin> PER! ! responsive!disorders;!CHO!Disorders!of!carbohydrate!metabolism;!LSD! Lysosomal!disorders;!NCL!Neuronal!ceroid!lipofuscinoses;!PER!Peroxisomal! -
Clinical and Molecular Characterization of Three Patients
Mahjoub et al. BMC Medical Genetics (2019) 20:167 https://doi.org/10.1186/s12881-019-0893-9 CASE REPORT Open Access Clinical and molecular characterization of three patients with Hepatocerebral form of mitochondrial DNA depletion syndrome: a case series Ghazale Mahjoub1, Parham Habibzadeh1,2, Hassan Dastsooz1,3, Malihe Mirzaei1, Arghavan Kavosi1, Laila Jamali1, Haniyeh Javanmardi2, Pegah Katibeh4, Mohammad Ali Faghihi1,5 and Seyed Alireza Dastgheib6* Abstract Background: Mitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis. Case presentation: In this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706–707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. -
Protection Against Apoptosis by Monoamine Oxidase a Inhibitors
View metadata,FEBS 20082 citation and similar papers at core.ac.uk FEBS Letters 426 (1998)brought to 155^159 you by CORE provided by Elsevier - Publisher Connector Protection against apoptosis by monoamine oxidase A inhibitors W. Malornia;*, A.M. Giammariolia, P. Matarresea, P. Pietrangelib, E. Agostinellib, A. Ciacciob, E. Grassillic, B. Mondovi'b aDepartment of Ultrastructures, Istituto Superiore di Sanitaé, Viale Regina Elena 299, 00161 Rome, Italy bDepartment of Biochemical Sciences and CNR Center of Molecular Biology, University of Rome `La Sapienza', Rome, Italy cDepartment of General Pathology, University of Modena, Modena, Italy Received 27 February 1998 mitochondrial membrane potential or apoptosis. Analytical Abstract Several lines of evidence have been accumulating indicating that an important role may be played by mitochondrial cytology analyses revealed that maintenance of the mitochon- homeostasis in the initiation phase, the first stage of apoptosis. drial homeostasis by pargyline and clorgyline is associated This work describes the results obtained by using different with a partial hindering of the apoptotic process. inhibitors of monoamine oxidases (MAO), i.e. pargyline, clorgyline and deprenyl, on mitochondrial integrity and apopto- 2. Materials and methods sis. Both pargyline and clorgyline are capable of protecting cells from apoptosis induced by serum starvation while deprenyl is 2.1. Cell cultures ineffective. These data represent the first demonstration that Human melanoma cells (M14) were grown in monolayer in modi- MAO-A inhibitors may protect cells from apoptosis through a ¢ed RPMI 1640 medium supplemented with 10% heat-inactivated mechanism involving the maintenance of mitochondrial homeo- fetal calf serum (FCS), 1 mM sodium pyruvate, 1% non-essential stasis. -
Regional Differences in Mitochondrial DNA Methylation in Human Post-Mortem Brain Tissue Matthew Devall1, Rebecca G
Devall et al. Clinical Epigenetics (2017) 9:47 DOI 10.1186/s13148-017-0337-3 SHORT REPORT Open Access Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue Matthew Devall1, Rebecca G. Smith1, Aaron Jeffries1,2, Eilis Hannon1, Matthew N. Davies3, Leonard Schalkwyk4, Jonathan Mill1,2, Michael Weedon1 and Katie Lunnon1* Abstract Background: DNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood. Results: We were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions (p < 0.05) in the mitochondrial genome, between anatomically separate cortical regions and the cerebellum in matched samples (N = 3 matched donors). Further analysis identified eight significant differentially methylated regions between the total cortex and cerebellum after correcting for multiple testing. -
Introduction Results Patients and Methods
Célia Nogueira 1, José Barros 2, Maria José Sá 3, Luísa Azevedo 4, Filippo M. Santorelli 5, Laura Vilarinho 1 1National Institute of Health, Genetics Department, INSA, Oporto, Portugal; 2Neurology Unit, Hospital S. António, Oporto, Portugal; 3Neurology Unit, Hospital S. João, Oporto, Portugal; 4IPATIMUP, Population Genetics, Oporto University, Oporto, Portugal; 5Fundazione Stella Maris, Molecular Medicine & Neurogenetics, IRCCS, Pisa, Italy. INTRODUCTION RESULTS Defects of mitochondrial complex III (CIII) are a relatively rare cause of We had first detected a biochemically deficient enzyme activity in the mitochondrial dysfunction. CIII or ubiquinol-cytochrome c reductase is family, we had analyzed all structural genes part of CIII as well as the third component of the mitochondrial respiratory chain and catalyzes BCS1L. Only the recent description of mutations in TTC19 raised high the electrons transfer from reduced coenzyme Q to cytochrome c and is the suspect of a similar condition in the present family. The novel composed of 11 subunits ; one encoded by mitochondrial DNA (MT -CYB ) TTC 19 mutation p.A321 AfsX 8 (c .962 _967 delTGGC), identified in this and the remaining by nuclear genes [1]. BCS1L gene is a CIII assembly family, was homozygous in the four patients, heterozygous in their factor. Mutations in MT-CYB and BCS1L genes account for the vast parents and in two healthy relatives, and it was absent in ethnically- majority of mutations leading to CIII deficiency, and are associated with matched controls (Figure 2). a wide range of neuromuscular disorders [2]. The human tetratricopeptide 19 (TTC19), encodes a poorly understood A B member of tetratricopeptide repeat domain 19 located on chromosome 17 and appears to be involved in the correct assembly of CIII. -
Mitochondrial Dysfunction in Parkinson's Disease: Focus on Mitochondrial
biomedicines Review Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA Olga Buneeva, Valerii Fedchenko, Arthur Kopylov and Alexei Medvedev * Institute of Biomedical Chemistry, 10 Pogodinskaya Street, 119121 Moscow, Russia; [email protected] (O.B.); [email protected] (V.F.); [email protected] (A.K.) * Correspondence: [email protected]; Tel.: +7-495-245-0509 Received: 17 November 2020; Accepted: 8 December 2020; Published: 10 December 2020 Abstract: Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models.