Progressive Increase in Mtdna 3243A>G Heteroplasmy Causes Abrupt
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(PI3K(P110 )) Directly Regulates Key Components of the Z-Disc And
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 35, pp. 30837–30846, September 2, 2011 © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A. Phosphoinositide 3-Kinase (PI3K(p110␣)) Directly Regulates Key Components of the Z-disc and Cardiac Structure*□S Received for publication, June 13, 2011, and in revised form, July 7, 2011 Published, JBC Papers in Press, July 11, 2011, DOI 10.1074/jbc.M111.271684 Ashley J. Waardenberg‡§, Bianca C. Bernardo¶, Dominic C. H. Ngʈ, Peter R. Shepherd**‡‡, Nelly Cemerlang¶, Mauro Sbroggio` §§, Christine A. Wells‡¶¶, Brian P. Dalrymple§, Mara Brancaccio§§, Ruby C. Y. Linʈʈ1, and Julie R. McMullen¶1,2 From the ‡Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland, 4111, Australia, §Commonwealth Scientific and Industrial Research Organisation, Food Futures Flagship, Queensland Bioscience Precinct, St. Lucia, Queensland, 4067, Australia, the ¶Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, 8008, Australia, the ʈDepartment of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, 3010, Australia, the **Department of Molecular Medicine, University of Auckland, Grafton, Auckland, 1142, New Zealand, the ‡‡Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Grafton, Auckland, 1142, New Zealand, the §§Department of Genetics, Biology, and Biochemistry, University of Torino, Molecular Biotechnology Center, Torino, 10126, Italy, the ¶¶Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, 4072, Australia, and the ʈʈRamaciotti Centre for Gene Function Analysis and the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, 2052, Australia Downloaded from Maintenance of cardiac structure and Z-disc signaling are key from PI3K transgenic mice. -
Stable and Widespread Structural Heteroplasmy in Chloroplast Genomes Revealed by a New Long-Read Quantification Method
bioRxiv preprint doi: https://doi.org/10.1101/692798; this version posted July 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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. Classification: Biological Sciences, Evolution Title: Stable and widespread structural heteroplasmy in chloroplast genomes revealed by a new long-read quantification method Weiwen Wang a, Robert Lanfear a a Research School of Biology, Australian National University, Canberra, ACT, Australia, 2601 Corresponding Author: Weiwen Wang, [email protected] Robert Lanfear, [email protected], +61 2 6125 2536 Keywords: Single copy inversion, flip-flop recombination, chloroplast genome structural heteroplasmy 1 bioRxiv preprint doi: https://doi.org/10.1101/692798; this version posted July 11, 2019. 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. 1 Abstract 2 The chloroplast genome usually has a quadripartite structure consisting of a large 3 single copy region and a small single copy region separated by two long inverted 4 repeats. It has been known for some time that a single cell may contain at least two 5 structural haplotypes of this structure, which differ in the relative orientation of the 6 single copy regions. However, the methods required to detect and measure the 7 abundance of the structural haplotypes are labour-intensive, and this phenomenon 8 remains understudied. -
Intra-Individual Heteroplasmy in the Gentiana Tongolensis Plastid Genome (Gentianaceae)
Intra-individual heteroplasmy in the Gentiana tongolensis plastid genome (Gentianaceae) Shan-Shan Sun1, Xiao-Jun Zhou1, Zhi-Zhong Li2,3, Hong-Yang Song1, Zhi-Cheng Long4 and Peng-Cheng Fu1 1 College of Life Science, Luoyang Normal University, Luoyang, Henan, People’s Republic of China 2 Key Laboratory of Aquatic Botany and Watershed Ecology, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan, Hubei, People’s Republic of China 3 University of Chinese Academy of Sciences, Beijing, People’s Republic of China 4 HostGene. Co. Ltd., Wuhan, Hubei, People’s Republic of China ABSTRACT Chloroplasts are typically inherited from the female parent and are haploid in most angiosperms, but rare intra-individual heteroplasmy in plastid genomes has been reported in plants. Here, we report an example of plastome heteroplasmy and its characteristics in Gentiana tongolensis (Gentianaceae). The plastid genome of G. tongolensis is 145,757 bp in size and is missing parts of petD gene when compared with other Gentiana species. A total of 112 single nucleotide polymorphisms (SNPs) and 31 indels with frequencies of more than 2% were detected in the plastid genome, and most were located in protein coding regions. Most sites with SNP frequencies of more than 10% were located in six genes in the LSC region. After verification via cloning and Sanger sequencing at three loci, heteroplasmy was identified in different individuals. The cause of heteroplasmy at the nucleotide level in plastome of G. tongolensis is unclear from the present data, although biparental plastid inheritance and transfer of plastid DNA seem to be most likely. This study implies that botanists should reconsider the heredity and evolution of chloroplasts and be 19 February 2019 Submitted cautious with using chloroplasts as genetic markers, especially in Gentiana. -
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. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Pharmacological Inhibition of Tumor Anabolism and Host Catabolism As A
www.nature.com/scientificreports OPEN Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy Alejandro Schcolnik‑Cabrera1,2, Alma Chavez‑Blanco1, Guadalupe Dominguez‑Gomez1, Mandy Juarez1, Ariana Vargas‑Castillo3, Rafael Isaac Ponce‑Toledo4, Donna Lai5, Sheng Hua5, Armando R. Tovar3, Nimbe Torres3, Delia Perez‑Montiel6, Jose Diaz‑Chavez1 & Alfonso Duenas‑Gonzalez1,7* The malignant energetic demands are satisfed through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic infammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their efect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These efects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a signifcant tumor volume inhibition, without damage to normal tissues. The six‑drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our fndings demonstrate that the simultaneous use of this six‑drug combination has anticancer efects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well‑ tolerated in mice and reduces whole animal energetic expenditure and fat loss. -
Core Human Mitochondrial Transcription Apparatus Is a Regulated Two-Component System in Vitro
Core human mitochondrial transcription apparatus is a regulated two-component system in vitro Timothy E. Shutta, Maria F. Lodeirob, Justin Cotneya, Craig E. Cameronb, and Gerald S. Shadela,c,1 aDepartment of Pathology, Yale University School of Medicine, 310 Cedar Street, P.O. Box 208023, New Haven, CT 06520-8023; bDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, 201 Althouse Laboratory, University Park, PA 16802; and cDepartment of Genetics, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208005, New Haven, CT 06520-8005 Edited by David A. Clayton, Howard Hughes Medical Institute, Ashburn, VA, and accepted by the Editorial Board May 25, 2010 (received for review September 15, 2009) The core human mitochondrial transcription apparatus is currently ribosomal proteins to generate mitochondrial ribosomes. Finally, regarded as an obligate three-component system comprising the transcripts from the LSP are also used as primers for mtDNA bacteriophage T7-related mitochondrial RNA polymerase, the rRNA replication (5, 6), thus LSP transcription serves a dual role in methyltransferase-related transcription factor, h-mtTFB2, and the gene expression and mtDNA maintenance (7, 8). high mobility group box transcription/DNA-packaging factor, Much effort has been devoted to identifying the core machin- h-mtTFA/TFAM. Using a faithful recombinant human mitochondrial ery needed for mitochondrial transcription in humans as a critical transcription system from Escherichia coli, we demonstrate that step toward understanding the mechanism of human mitochon- specific initiation from the mtDNA promoters, LSP and HSP1, only drial gene expression and replication in vivo and its role in human requires mitochondrial RNA polymerase and h-mtTFB2 in vitro. -
Robert Shine, Peter Dwyer, Lyndsay Olson, Jennifer Truong, Matthew Goddeeris, Effie Tozzo, Eric Bell Mitobridge, Inc
Poster Title Here Mitochondrial Deficiency in Primary Muscle Cells from Mdx Mice Robert Shine, Peter Dwyer, Lyndsay Olson, Jennifer Truong, Matthew Goddeeris, Effie Tozzo, Eric Bell Mitobridge, Inc. Cambridge, MA 02138 Abstract Results Results Duchenne muscular dystrophy (DMD) is a recessive, fatal X-linked disease that is characterized M ito c h o n d ria l c o n trib u te d A T P is re d u c e d Mdx myoblasts have decreased expression by progressive skeletal muscle wasting due to a loss of function in dystrophin, a protein that is of OXPHOS complexes part of a complex that bridges the cytoskeleton and extracellular matrix. The mdx mouse, an in m d x m y o b la s ts a n d m y o tu b e s T animal model for DMD, has a point mutation in the dystrophin gene that results in a loss of 1 .5 2.0 W l function. This study uses primary muscle satellite cell derived myoblasts and myotubes to W T a WT m determine differences in mitochondrial biology between the mdx mice and wild type (WT) control s M D X o 1.5 a r MDX mice. Compared to cells isolated from WT mice, mdx cells have reductions in mitochondrial 1 .0 **** f B bioenergetics. Moreover, mdx cells have reduced levels of mitochondria which may partially *** e T g 1.0 explain the reduction in bioenergetics. Interestingly, the mitochondrial phenotype is apparent **** ** n * * W a * * * before dystrophin protein is increased during myogenesis. * * * 0 .5 h 0.5 * d l C o d l F 0.0 o 1 3 2 6 1 a 1 a b B 0 .0 F t v Materials and Analysis a 5 P X D C H H y 5 l l F X T N R O D a M in a M in D C s s P n n U A c c O S C C a 0 a 0 S y y T B 0 B 0 D WT and mdx myoblast isolation and culture: Quadricep and gastrocnemius muscles from a C 1 m 1 m Q A o o N single mouse were pooled and subjected to a mechanical/collagenase digestion. -
Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: an Update
International Journal of Molecular Sciences Review Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update Philippe Icard 1,2,3,*, Antoine Coquerel 1,4, Zherui Wu 5 , Joseph Gligorov 6, David Fuks 7, Ludovic Fournel 3,8, Hubert Lincet 9,10 and Luca Simula 11 1 Medical School, Université Caen Normandie, CHU de Caen, 14000 Caen, France; [email protected] 2 UNICAEN, INSERM U1086 Interdisciplinary Research Unit for Cancer Prevention and Treatment, Normandie Université, 14000 Caen, France 3 Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, APHP, Paris-Descartes University, 75014 Paris, France; [email protected] 4 INSERM U1075, COMETE Mobilités: Attention, Orientation, Chronobiologie, Université Caen, 14000 Caen, France 5 School of Medicine, Shenzhen University, Shenzhen 518000, China; [email protected] 6 Oncology Department, Tenon Hospital, Pierre et Marie Curie University, 75020 Paris, France; [email protected] 7 Service de Chirurgie Digestive et Hépato-Biliaire, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, APHP, Paris-Descartes University, 75014 Paris, France; [email protected] 8 Descartes Faculty of Medicine, University of Paris, Paris Center, 75006 Paris, France 9 INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; [email protected] 10 ISPB, Faculté de Pharmacie, Université Lyon 1, 69373 Lyon, France 11 Department of Infection, Immunity and Inflammation, Institut Cochin, INSERM U1016, CNRS UMR8104, Citation: Icard, P.; Coquerel, A.; Wu, University of Paris, 75014 Paris, France; [email protected] Z.; Gligorov, J.; Fuks, D.; Fournel, L.; * Correspondence: [email protected] Lincet, H.; Simula, L. -
PIM2-Mediated Phosphorylation of Hexokinase 2 Is Critical for Tumor Growth and Paclitaxel Resistance in Breast Cancer
Oncogene (2018) 37:5997–6009 https://doi.org/10.1038/s41388-018-0386-x ARTICLE PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer 1 1 1 1 1 2 2 3 Tingting Yang ● Chune Ren ● Pengyun Qiao ● Xue Han ● Li Wang ● Shijun Lv ● Yonghong Sun ● Zhijun Liu ● 3 1 Yu Du ● Zhenhai Yu Received: 3 December 2017 / Revised: 30 May 2018 / Accepted: 31 May 2018 / Published online: 9 July 2018 © The Author(s) 2018. This article is published with open access Abstract Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer. Furthermore, phosphorylation of HK2 on Thr473 increased HK2 enzyme activity and glycolysis, and 1234567890();,: 1234567890();,: enhanced glucose starvation-induced autophagy. As a result, phosphorylated HK2 Thr473 promoted breast cancer cell growth in vitro and in vivo. Interestingly, PIM2 kinase inhibitor SMI-4a could abrogate the effects of phosphorylated HK2 Thr473 on paclitaxel resistance in vitro and in vivo. Taken together, our findings indicated that PIM2 was a novel regulator of HK2, and suggested a new strategy to treat breast cancer. Introduction ATP molecules. -
Identification of Transcriptomic Differences Between Lower
International Journal of Molecular Sciences Article Identification of Transcriptomic Differences between Lower Extremities Arterial Disease, Abdominal Aortic Aneurysm and Chronic Venous Disease in Peripheral Blood Mononuclear Cells Specimens Daniel P. Zalewski 1,*,† , Karol P. Ruszel 2,†, Andrzej St˛epniewski 3, Dariusz Gałkowski 4, Jacek Bogucki 5 , Przemysław Kołodziej 6 , Jolanta Szyma ´nska 7 , Bartosz J. Płachno 8 , Tomasz Zubilewicz 9 , Marcin Feldo 9,‡ , Janusz Kocki 2,‡ and Anna Bogucka-Kocka 1,‡ 1 Chair and Department of Biology and Genetics, Medical University of Lublin, 4a Chod´zkiSt., 20-093 Lublin, Poland; [email protected] 2 Chair of Medical Genetics, Department of Clinical Genetics, Medical University of Lublin, 11 Radziwiłłowska St., 20-080 Lublin, Poland; [email protected] (K.P.R.); [email protected] (J.K.) 3 Ecotech Complex Analytical and Programme Centre for Advanced Environmentally Friendly Technologies, University of Marie Curie-Skłodowska, 39 Gł˛ebokaSt., 20-612 Lublin, Poland; [email protected] 4 Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019, USA; [email protected] 5 Chair and Department of Organic Chemistry, Medical University of Lublin, 4a Chod´zkiSt., Citation: Zalewski, D.P.; Ruszel, K.P.; 20-093 Lublin, Poland; [email protected] St˛epniewski,A.; Gałkowski, D.; 6 Laboratory of Diagnostic Parasitology, Chair and Department of Biology and Genetics, Medical University of Bogucki, J.; Kołodziej, P.; Szyma´nska, Lublin, 4a Chod´zkiSt., 20-093 Lublin, Poland; [email protected] J.; Płachno, B.J.; Zubilewicz, T.; Feldo, 7 Department of Integrated Paediatric Dentistry, Chair of Integrated Dentistry, Medical University of Lublin, M.; et al. -
Branched Chain A-Ketoacid Dehydrogenase to Thiamine and Thiamine Pyrophosphate
Pediat. Res. 12: 235-238 (1978) Branched chain amino acids thiamine maple syrup urine disease vitamin responsiveness mitochondrial membranes In Vivo and in Vitro Response of Human Branched Chain a-Ketoacid Dehydrogenase to Thiamine and Thiamine Pyrophosphate DEAN J. DANNER,'27' FRANCES B. WHEELER, SANDRA K. LEMMON, AND LOUIS J. ELSAS I1 Department of Pediatrics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA Summary lability at 37"; and failure to respond to added NAD+, CoASH, and MgZ+. In a homozygous affected patient with maple syrup urine We propose that "excess" thiamine led to increased available disease, pharmacologic doses of thiamine lowered urinary excre- thiamine pyrophosphate which stabilized the branched chain a- tion of branched chain a-ketoacids and stimulated branched ketoacid dehydrogenase, decreased biologic turnover, increased chain a-ketoacid dehydrogenase (BCKAD) in his peripheral enzyme specific activity and produced in vivo tolerance to blood leukocvtes. Suvvlementation of his branched chain ami- branched chain aminoacids in these patients with maple syrup noacid restricted diei hth 100 mglday of thiamine eliminated urine disease. recurrent episodes of ketoacidosis.~heseclinical responses were Speculation studied in vitro using mitochondria1 inner membranes prepared from his cultured skin fibroblasts and those from another By studying the partially purified normal and mutant branched thiamine-responsive patient from Canada. BCKAD in both chain a-ketoacid dehydrogenases from cultured human fibro- mutant cell lines had similarities to normal enzyme including: blasts, direct in vitro effects of thiamine pyrophosphate can be identical apparent K,,, value for thiamine pyrophosphate; similar measured and related to in vivo clinical responses.