DOCSLIB.ORG

Intimate Relations—Mitochondria and Ageing

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Intimate Relations—Mitochondria and Ageing International Journal of Molecular Sciences Review Intimate Relations—Mitochondria and Ageing Michael Webb and Dionisia P. Sideris * Mitobridge Inc., an Astellas Company, 1030 Massachusetts Ave, Cambridge, MA 02138, USA; [email protected] * Correspondence: [email protected] Received: 29 August 2020; Accepted: 6 October 2020; Published: 14 October 2020 Abstract: Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. Wereview the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction. Keywords: mitochondria; ageing; energetics; ROS; gene regulation 1. Introduction The last two decades have witnessed a dramatic transformation in our view of mitochondria, their basic biology and functions. While still regarded as functioning primarily as the eukaryotic cell’s generator of energy in the form of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (reduced form; NADH), mitochondria are now recognized as having a plethora of functions, including control of apoptosis, regulation of calcium, forming a signaling hub and the synthesis of various bioactive molecules. Their biochemical functions beyond ATP supply include biosynthesis of lipids and amino acids, formation of iron sulphur complexes and some stages of haem biosynthesis and the urea cycle. They exist as a dynamic network of organelles that under normal circumstances undergo a constant series of fission and fusion events in which structural, functional and encoding (mtDNA) elements are subject to redistribution throughout the network. These processes are intimately linked to the health of the mitochondrion and it would not be an exaggeration to state that the health of the cell is a reflection of the health of its mitochondria. The endosymbiotic hypothesis for the origin of mitochondria from aerobic bacteria engulfed by the primitive eukaryotic cell was originally proposed by Sagan [1] and has now gained general support. During their 1.45 billion years of co-evolution, most of the endosymbiont’s genes have been transferred to the nucleus of the host cell and of the approximately 1500 proteins that constitute the mitochondrial proteome, only a minority are encoded by mtDNA. In mammals mtDNA encodes 13 proteins of the electron transport chain, 22 mitochondrial specific tRNAs and two ribosomal RNAs. This distribution of genes across two genomes clearly implies a co-ordinate regulation of the activities of nuclear and mitochondrial genes [2]. Mutations in mitochondrial DNA are causative of several disorders with specific clinical manifestations and declining mitochondrial function, reflected in defects in ATP synthesis and increased generation of toxic reactive oxygen species is a universal feature of natural ageing. It accompanies the other hallmarks of ageing which include progressive loss of function in multiple organs, sarcopenia and increasing maladaptive low-grade inflammation. These end in death, which is a cumulative result of loss of function, leading to either increased vulnerability to environmental hazards such as predation and disease or to failure of critical organ systems such as the heart, liver or kidney. Several processes Int. J. Mol. Sci. 2020, 21, 7580; doi:10.3390/ijms21207580 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7580 2 of 50 that may contribute mechanistically to age related degeneration have been identified, including oxidative damage, accumulation of toxic protein aggregates, autoinflammatory processes, loss of stem cell populations and an increasing load of malfunctional senescent cells. Are these processes linked to declining mitochondrial function and if so, is there a cause and effect relationship? if so, in which direction does it operate? MitochondriaInt. J. Mol. Sci.generate 2020, 21, x FOR reactive PEER REVIEW oxygen species (ROS) as a consequence of the electron2 of 48 transport that drives oxidative ATP synthesis. These have a dual aspect, functioning at low levels as an important or kidney. Several processes that may contribute mechanistically to age related degeneration have communication system regulating multiple cellular responses but also directly damaging macromolecules been identified, including oxidative damage, accumulation of toxic protein aggregates, to a degreeautoinflammatory proportional to processes, their proximity loss of stem to high cell populations ROS concentrations. and an increasing Thus, loadmitochondrial of malfunctional components, proteins, lipidssenescent and cells. carbohydrates, Are these processes are linked all subjectto declining to mitochondrial accumulating function ROS and damage if so, is there which a impairs mitochondrialcause and function. effect relationship? This impairment if so, in which of direction function does by it operate? damaged molecules is reduced by two Mitochondria generate reactive oxygen species (ROS) as a consequence of the electron transport mechanisms,that (1)drives their oxidative redistribution ATP synthesis. and dilutionThese have by a thedual same aspect, fission functioning/fusion at low process levels that as an distributes newly synthesizedimportant communication components andsystem (2) regulating the selective multiple elimination cellular responses of mitochondria but also directly which damaging have acquired sufficient damagemacromolecules by a macroautophagic to a degree proportional process to thei knownr proximity as mitophagy. to high ROS concentrations. Thus, Mitochondrialmitochondrial quality components, is proteins, therefore lipids maintained and carbohydrates, by are the all subject linked to accumulating process of ROS biogenesis, damage which impairs mitochondrial function. This impairment of function by damaged molecules dynamic fissionis reduced/fusion by two and mechanisms, mitophagy (1) their and redistributi their importanceon and dilution is indicatedby the same byfission/fusion the fact thatprocess impairment of any of themthat distributes is associated newly withsynthesized poor cellcomponents function and and (2) the viability. selective Theseelimination processes of mitochondria operate in a time scale of minuteswhich have to hours acquired and sufficient yet mitochondrial damage by a macroautophagic function nevertheless process known declines as mitophagy. over decades with age. This can be seenMitochondrial in many diqualityfferent is therefore parameters maintained including by the decreases linked process in ATP, of biogenesis, changes dynamic in the activity of fission/fusion and mitophagy and their importance is indicated by the fact that impairment of any of electron transportthem is associated and mitochondrial with poor cell enzymesfunction and such viability. as citrate These processes synthase, operate reduced in a time respiratory scale of capacity, changes inminutes substrate to hours preference, and yet mitochondrial increasing function accumulation nevertheless of mutations declines over in decades mtDNA with and age. lossThis of overall mitochondrialcan be mass seen in [3 –many5]. Thisdifferent raises parameters the question including of decreases why mitochondrial in ATP, changes quality in the activity control of processes increasinglyelectron fail totransport compensate and mitochondrial for age relatedenzymes declinessuch as citrate in mitochondrialsynthase, reduced functionrespiratory andcapacity, indeed some changes in substrate preference, increasing accumulation of mutations in mtDNA and loss of overall evidence suggestsmitochondrial that mass these [3–5]. processes This raises themselves the question become of why mitochondrial less efficient quality with control age. processes Simplerincreasingly eukaryotes fail to such compensate as yeast for and age relatedC. elegans declineshave in beenmitochondrial invaluable function in unraveling and indeed some the molecular details of mitochondrialevidence suggestsbiology, that these suchprocesses as dynamics themselves become and the less mitochondrial efficient with age. unfolded protein response. However, as unicellularSimpler eukaryotes (yeast) such and as largely yeast post-mitoticand C. elegans (haveC. elegans been )invaluable organisms, in unraveling they cannot the represent molecular details of mitochondrial biology, such as dynamics and the mitochondrial unfolded the complexityprotein of response. the mammal, However, with as unicellular its differentiated (yeast) and celllargely types post-mitotic and organ (C. elegans systems,) organisms, homeothermy they and mix of mitoticcannot and represent post mitoticthe complexity cells. of We the willmammal, therefore with its refer differentiated to results cell from types simplerand organ organismssystems, where germane buthomeothermy focus most and mix of the of mitotic discussion and post on mitotic data cells. from We will mammals. therefore refer We to will results consider from simpler here only the processes andorganisms mechanisms where germane relating but naturalfocus most ageing of the discussion to mitochondria on data from and mammals. interventions We will toconsider extend lifespan here only the processes and mechanisms relating natural ageing
Load more

Recommended publications
  • Old Data and Friends Improve with Age: Advancements with the Updated Tools of Genenetwork
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445383; this version posted May 25, 2021. 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 4.0 International license. Old data and friends improve with age: Advancements with the updated tools of GeneNetwork Alisha Chunduri1, David G. Ashbrook2 1Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad 500075, India 2Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA Abstract Understanding gene-by-environment interactions is important across biology, particularly behaviour. Families of isogenic strains are excellently placed, as the same genome can be tested in multiple environments. The BXD’s recent expansion to 140 strains makes them the largest family of murine isogenic genomes, and therefore give great power to detect QTL. Indefinite reproducible genometypes can be leveraged; old data can be reanalysed with emerging tools to produce novel biological insights. To highlight the importance of reanalyses, we obtained drug- and behavioural-phenotypes from Philip et al. 2010, and reanalysed their data with new genotypes from sequencing, and new models (GEMMA and R/qtl2). We discover QTL on chromosomes 3, 5, 9, 11, and 14, not found in the original study. We narrowed down the candidate genes based on their ability to alter gene expression and/or protein function, using cis-eQTL analysis, and variants predicted to be deleterious. Co-expression analysis (‘gene friends’) and human PheWAS were used to further narrow candidates.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Domain of Escherichia Coli 16S Ribosomal RNA Using Site-Directed Photoaffinity Crosslinking
    Downloaded from rnajournal.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press RNA (1998), 4:1455–1466+ Cambridge University Press+ Printed in the USA+ Copyright © 1998 RNA Society+ Analysis of the conformation of the 39 major domain of Escherichia coli 16S ribosomal RNA using site-directed photoaffinity crosslinking ALEXANDRE MONTPETIT,1 CATHERINE PAYANT,1 JAMES M. NOLAN,2 and LÉA BRAKIER-GINGRAS1 1Département de Biochimie, Université de Montréal, Montréal, Québec H3T 1J4, Canada 2Department of Biochemistry, Tulane University Medical Center, New Orleans, Louisiana 70112, USA ABSTRACT The 39 major domain of Escherichia coli 16S rRNA, which occupies the head of the small ribosomal subunit, is involved in several functions of the ribosome. We have used a site-specific crosslinking procedure to gain further insights into the higher-order structure of this domain. Circularly permuted RNAs were used to introduce an azi- dophenacyl group at specific positions within the 39 major domain. Crosslinks were generated in a high-ionic strength buffer that has been used for ribosome reconstitution studies and so enables the RNA to adopt a structure recognized by ribosomal proteins. The crosslinking sites were identified by primer extension and confirmed by assessing the mobility of the crosslinked RNA lariats in denaturing polyacrylamide gels. Eight crosslinks were characterized. Among them, one crosslink demonstrates that helix 28 is proximal to the top of helix 34, and two others show that the 1337 region, located in an internal loop at the junction of helices 29, 30, 41, and 42, is proximal to the center of helix 30 and to a segment connecting helix 28 to helix 29.
    [Show full text]
  • Nuclear ELAC2 Overexpression Is Associated with Increased Hazard for Relapse After Radical Prostatectomy
    www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 48), pp: 4973-4986 Research Paper Nuclear ELAC2 overexpression is associated with increased hazard for relapse after radical prostatectomy Cornelia Schroeder1,2,*, Elham Navid-Hill1,*, Jan Meiners2, Claudia Hube-Magg1, Martina Kluth1, Georgia Makrypidi-Fraune1, Ronald Simon1, Franziska Büscheck1, Andreas M. Luebke1, Cosima Goebel1, Dagmar S. Lang1, Sören Weidemann1, Emily Neubauer1, Andrea Hinsch1, Frank Jacobsen1, Patrick Lebok1, Uwe Michl3, Dirk Pehrke3,4, Hartwig Huland3, Markus Graefen3, Thorsten Schlomm3,4, Guido Sauter1 and Doris Höflmayer1 1Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 3Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4Department of Urology, Charité - Universitätsmedizin Berlin, Berlin, Germany *These authors contributed equally to this work Correspondence to: Ronald Simon, email: [email protected] Keywords: ELAC2; HPC2; prostate cancer; prognosis; tissue microarray Received: November 17, 2018 Accepted: July 21, 2019 Published: August 13, 2019 Copyright: Schroeder et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT ELAC2 is a ubiquitously expressed enzyme potentially involved in tRNA processing and cell signaling pathways. Mutations of the ELAC2 gene have been found to confer increased prostate cancer susceptibility in families. ELAC2 protein expression was analyzed by immunohistochemistry in 9,262 patients and Kaplan-Meier curves of PSA recurrence-free survival were calculated in 8,513 patients treated with radical prostatectomy.
    [Show full text]
  • Mitochondrial Supercomplex Assembly Promotes Breast and Endometrial Tumorigenesis by Metabolic Alterations and Enhanced Hypoxia Tolerance
    ARTICLE https://doi.org/10.1038/s41467-019-12124-6 OPEN Mitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance Kazuhiro Ikeda1, Kuniko Horie-Inoue1, Takashi Suzuki2, Rutsuko Hobo1,3, Norie Nakasato1,3, Satoru Takeda3,4 & Satoshi Inoue 1,5 1234567890():,; Recent advance in cancer research sheds light on the contribution of mitochondrial respiration in tumorigenesis, as they efficiently produce ATP and oncogenic metabolites that will facilitate cancer cell growth. Here we show that a stabilizing factor for mitochondrial supercomplex assembly, COX7RP/COX7A2L/SCAF1, is abundantly expressed in clinical breast and endometrial cancers. Moreover, COX7RP overexpression associates with prog- nosis of breast cancer patients. We demonstrate that COX7RP overexpression in breast and endometrial cancer cells promotes in vitro and in vivo growth, stabilizes mitochondrial supercomplex assembly even in hypoxic states, and increases hypoxia tolerance. Metabo- lomic analyses reveal that COX7RP overexpression modulates the metabolic profile of cancer cells, particularly the steady-state levels of tricarboxylic acid cycle intermediates. Notably, silencing of each subunit of the 2-oxoglutarate dehydrogenase complex decreases the COX7RP-stimulated cancer cell growth. Our results indicate that COX7RP is a growth- regulatory factor for breast and endometrial cancer cells by regulating metabolic pathways and energy production. 1 Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan. 2 Departments of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. 3 Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, 1981, Tsujido, Kamoda, Kawagoe-shi, Saitama 350-8550, Japan.
    [Show full text]
  • A Yeast Phenomic Model for the Influence of Warburg Metabolism on Genetic Buffering of Doxorubicin Sean M
    Santos and Hartman Cancer & Metabolism (2019) 7:9 https://doi.org/10.1186/s40170-019-0201-3 RESEARCH Open Access A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin Sean M. Santos and John L. Hartman IV* Abstract Background: The influence of the Warburg phenomenon on chemotherapy response is unknown. Saccharomyces cerevisiae mimics the Warburg effect, repressing respiration in the presence of adequate glucose. Yeast phenomic experiments were conducted to assess potential influences of Warburg metabolism on gene-drug interaction underlying the cellular response to doxorubicin. Homologous genes from yeast phenomic and cancer pharmacogenomics data were analyzed to infer evolutionary conservation of gene-drug interaction and predict therapeutic relevance. Methods: Cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library were measured by quantitative high-throughput cell array phenotyping (Q-HTCP), treating with escalating doxorubicin concentrations under conditions of respiratory or glycolytic metabolism. Doxorubicin-gene interaction was quantified by departure of CPPs observed for the doxorubicin-treated mutant strain from that expected based on an interaction model. Recursive expectation-maximization clustering (REMc) and Gene Ontology (GO)-based analyses of interactions identified functional biological modules that differentially buffer or promote doxorubicin cytotoxicity with respect to Warburg metabolism. Yeast phenomic and cancer pharmacogenomics data were integrated to predict differential gene expression causally influencing doxorubicin anti-tumor efficacy. Results: Yeast compromised for genes functioning in chromatin organization, and several other cellular processes are more resistant to doxorubicin under glycolytic conditions. Thus, the Warburg transition appears to alleviate requirements for cellular functions that buffer doxorubicin cytotoxicity in a respiratory context.
    [Show full text]
  • 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.
    [Show full text]
  • Study of Stem Cell Function Using Microarray Experiments
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS 29359 FEBS Letters 579 (2005) 1795–1801 Minireview Study of stem cell function using microarray experiments Carolina Perez-Iratxeta, Gareth Palidwor, Christopher J. Porter, Neal A. Sanche, Matthew R. Huska, Brian P. Suomela, Enrique M. Muro, Paul M. Krzyzanowski, Evan Hughes, Pearl A. Campbell, Michael A. Rudnicki, Miguel A. Andrade* Ontario Genomics Innovation Centre, Ottawa Health Research Institute, Molecular Medicine Program, 501 Smyth Road, Ottawa, Canada K1H 8L6 Accepted 10 February 2005 Available online 21 February 2005 Edited by Robert Russell and Giulio Superti-Furga If we understand the variety of cells of an organism as dif- Abstract DNA Microarrays are used to simultaneously mea- sure the levels of thousands of mRNAs in a sample. We illustrate ferent expressions of the same genome, it is clear that a collec- here that a collection of such measurements in different cell types tion of cell gene expression snapshots can give us information and states is a sound source of functional predictions, provided about that cell and of the relations between its genomeÕs the microarray experiments are analogous and the cell samples genes. For example, the concerted expression of two genes are appropriately diverse. We have used this approach to study across many cellular states would indicate their functional stem cells, whose identity and mechanisms of control are not well relation, even in the total absence of any other experimental understood, generating Affymetrix microarray data from more characterization. But to make this analysis meaningful two than 200 samples, including stem cells and their derivatives, from conditions apply to the gene expression data; it must be both human and mouse.
    [Show full text]
  • End Strand of Gene Gene Name Gene Function Starnd of Trascript
    Genomic TSS strand Gene starnd of Transcipt relatively to TSS Start End Gene name coordinates relatively TSS type Control_fwd TEX_fwd Control_rev TEX_rev of gene function trascript gene group of TSS to ATG ribosomal 93 854 + rps12 + 1 protein S12 1 1 14.0638317 20.7539794 0 0 93 324 exon 1 + 111 rps12 intron 1 1 13.90756687 18.07149224 0.781323982 0.423550599 829 854 exon 2 + 496 rps12 exon2 2 24.22104343 15.24782157 0 0 30S 904 1371 + gene rps7 ribosomal + 2 protein S7 1303 -209 rps7 inter (ndhB) 2 20.47068832 9.035746118 0.625059185 0.847101199 NADH dehydrogen 1512 3535 + gene ndhB (ndh2) + ase subunit 3 2 1696 ndhB exon 1-inter 2 3.594090315 2.964854195 0.468794389 0.282367066 + 2209 ndhB exon 1-inter 2 46.09811492 4.09432246 0.468794389 0.423550599 1512 2237 exon 1 + 2756 ndhB exon 2 -inter 2 43.28534858 4.800240125 0.312529593 0.282367066 2756 3535 exon 2 + 3090 ndhB exon 2 -inter 2 17.50165719 15.95373924 0.312529593 0 + 3192 ndhB exon 2 -inter 2 140.6383167 117.6058831 2.812766334 1.694202397 - 3462 ndhB exon 2 -inter 3 1.406383167 1.129468265 1.406383167 3.67077186 4 3633 3712 + tRNA tRNA-Leu-CAA + 3610 -23 tRNA-Leu 1 77.19480938 84.85130339 0.625059185 0 + 3633 1 tRNA-Leu 1 359.5652963 649.0207016 0.781323982 0 photosyste 3954 4058 + gene psbM m II protein + 5 M 3775 -179 psbM 2 20.47068832 12.00060031 0 0.141183533 + 3954 psbM-0 2 69.22530477 28.37789015 0.156264796 0 hypothetical 4182 5073 + gene ycf66 6 protein 4182 4287 exon 1 4772 5073 exon 2 7 5202 5113 - gene ycf (ORF29) - 5299 orf29 inter 1 0 0 3.125295926 3.67077186
    [Show full text]
  • THE FUNCTIONAL SIGNIFICANCE of MITOCHONDRIAL SUPERCOMPLEXES in C. ELEGANS by WICHIT SUTHAMMARAK Submitted in Partial Fulfillment
    THE FUNCTIONAL SIGNIFICANCE OF MITOCHONDRIAL SUPERCOMPLEXES in C. ELEGANS by WICHIT SUTHAMMARAK Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Drs. Margaret M. Sedensky & Philip G. Morgan Department of Genetics CASE WESTERN RESERVE UNIVERSITY January, 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Dedicated to my family, my teachers and all of my beloved ones for their love and support ii ACKNOWLEDGEMENTS My advanced academic journey began 5 years ago on the opposite side of the world. I traveled to the United States from Thailand in search of a better understanding of science so that one day I can return to my homeland and apply the knowledge and experience I have gained to improve the lives of those affected by sickness and disease yet unanswered by science. Ultimately, I hoped to make the academic transition into the scholarly community by proving myself through scientific research and understanding so that I can make a meaningful contribution to both the scientific and medical communities. The following dissertation would not have been possible without the help, support, and guidance of a lot of people both near and far. I wish to thank all who have aided me in one way or another on this long yet rewarding journey. My sincerest thanks and appreciation goes to my advisors Philip Morgan and Margaret Sedensky.
    [Show full text]
  • WO 2016/200987 Al 15 December 2016 (15.12.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/200987 Al 15 December 2016 (15.12.2016) P O P C T (51) International Patent Classification: Trudi, A.; Indigo Agriculture, Inc., 500 Rutherford Aven A01N 63/02 (2006.01) A01C 1/00 (2006.01) ue, North Building, Boston, MA 02129 (US). A01N 63/00 (2006.01) A01C 1/06 (2006.01) (74) Agents: HUBL, Susan, T. et al; Fenwick & West LLP, (21) International Application Number: Silicon Valley Center, 801 California Street, Mountain PCT/US20 16/036504 View, CA 94041 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 8 June 2016 (08.06.2016) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (25) Filing Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (26) Publication Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, N , IR, IS, JP, KE, KG, KN, KP, KR, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 62/172,748 8 June 2015 (08.06.2015) US MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 62/172,750 8 June 2015 (08.06.2015) US PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/172,755 8 June 2015 (08.06.2015) us SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/3 16,386 31 March 2016 (3 1.03.2016) us TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • Linoleic Acid Improves Assembly of the CII Subunit and CIII2/CIV
    Maekawa et al. Cell Communication and Signaling (2019) 17:128 https://doi.org/10.1186/s12964-019-0445-0 RESEARCH Open Access Linoleic acid improves assembly of the CII subunit and CIII2/CIV complex of the mitochondrial oxidative phosphorylation system in heart failure Satoshi Maekawa1, Shingo Takada1,2,3* , Hideo Nambu1, Takaaki Furihata1, Naoya Kakutani1,4, Daiki Setoyama5, Yasushi Ueyanagi5,6, Dongchon Kang5,6, Hisataka Sabe2† and Shintaro Kinugawa1† Abstract Background: Linoleic acid is the major fatty acid moiety of cardiolipin, which is central to the assembly of components involved in mitochondrial oxidative phosphorylation (OXPHOS). Although linoleic acid is an essential nutrient, its excess intake is harmful to health. On the other hand, linoleic acid has been shown to prevent the reduction in cardiolipin content and to improve mitochondrial function in aged rats with spontaneous hypertensive heart failure (HF). In this study, we found that lower dietary intake of linoleic acid in HF patients statistically correlates with greater severity of HF, and we investigated the mechanisms therein involved. Methods: HF patients, who were classified as New York Heart Association (NYHA) functional class I (n = 45), II (n = 93), and III (n = 15), were analyzed regarding their dietary intakes of different fatty acids during the one month prior to the study. Then, using a mouse model of HF, we confirmed reduced cardiolipin levels in their cardiac myocytes, and then analyzed the mechanisms by which dietary supplementation of linoleic acid improves cardiac malfunction of mitochondria. Results: The dietary intake of linoleic acid was significantly lower in NYHA III patients, as compared to NYHA II patients.
    [Show full text]