REDOX HOMEOSTASIS GROUP
ANTONIO MIRANDA-VIZUETE LAB
REDOX HOMEOSTASIS GROUP
Maintenance of redox homeostasis is critical for the survival of all organisms and, consequently, imbalances of redox homeostasis underlie many human pathologies. The thioredoxin (TRX) and glutathione/glutaredoxin (GSH/GRX) systems are the two main enzymatic systems that regulate redox homeostasis. However, there is still a fundamental lack of knowledge on the molecular mechanisms and pathways by which these two systems control cellular redox status. Our group uses the model organism Caenorhabditis elegans to gain deeper insight at the molecular, cellular and genetic level into the function of the metazoan thioredoxin and glutathione/glutaredoxin systems.
We are in Seville, one of the most beautiful cities around the world (Lonely Planet Best City to Travel 2018). Our lab is located at Seville Biomedicine Institute, a Research Center within the largest University Hospital Campus in Southern Spain. Importantly, we have five more groups in Seville working with C. elegans (being the most numerous worm community in Spain), with whom we have monthly meetings and several fruitful collaborations.
ELUCIDATING THE FUNCTION OF TRX-1 IN THE ASJ SENSORY NEURONS
C. elegans TRX-1 is the closest orthologue of human TRX-1. While human TRX-1 is ubiquitously expressed in the cytoplasm of all cells, worm TRX-1 is only expressed in the two ASJ sensory neurons. ASJ neurons regulate dauer formation and exit, longevity, cold habituation, phototaxis, male behaviour or pathogen avoidance and TRX-1 has been shown to participate in some of these phenotypes. However, we still do not know how TRX-1 works, which are its substrates and how it signals cell-non autonomously to regulate systemic responses.
ROLE OF THE GLUTATHIONE SYSTEM ON PROTEIN AGGREGATION
We have recently found that mutations in the gsr-1 gene, encoding glutathione reductase, enhance the deleterious phenotypes of worms expressing aggregation-prone proteins. gsr-1 mutants abolish the nuclear translocation of the HLH-30/TFEB transcription factor, a key inducer of autophagy. Thus, grs-1 mutants increase protein aggregation by inhibiting autophagy-dependent protein degradation. We want to elucidate the molecular mechanism by which glutathione reductase and glutathione regulate HLH-30 subcellular localization and function.
CHARACTERIZATION OF NOVEL MEMBERS OF THE C. ELEGANS TRX AND GRX SYSTEMS
The C. elegans genome encodes at least eight thioredoxin and five glutaredoxin proteins. However, only a few of them have been studied to date. We aim to fully characterize the remaining members of these two systems in C. elegans. For this purpose, we will first generate transgenic strains expressing GFP/DsRED under the control of their respective promoters to determine their respective expression patterns. In addition, we will use already available or newly generated mutants by CRISPR technology to identify their biological functions.
IDENTIFYING NOVEL REDOX REGULATORS OF PROTEOSTASIS
Worms expressing aggregating proteins display a lethal phenotype when exposed to sublethal doses of diethyl maleate (DEM), a GSH depletor agent. Genetic screens carried out in these worm models of protein aggregation have identified suppressor mutations that allow animals to grow at lethal doses of DEM. With this project, we aim to idenfity the molecular lesions responsible for these suppression phenotypes and to characterize the function of the mutated genes. We anticipate that this project will likely identitfy novel redox regulated pathways relevant to proteostasis maintenance.
Cell Death Differ. 2019 Sep;26(9):1545-1565.
LOSS OF GLUTATHIONE REDOX HOMEOSTASIS IMPAIRS PROTEOSTASIS BY INHIBITING AUTOPHAGY-DEPENDENT PROTEIN DEGRADATION.
Guerrero-Gómez D, Mora-Lorca JA, Sáenz-Narciso B, Naranjo-Galindo FJ, Muñoz-Lobato F, Parrado-Fernández C, Goikolea J, Cedazo-Minguez Á, Link CD, Neri C, Sequedo MD, Vázquez-Manrique RP, Fernández-Suárez E, Goder V, Pané R, Cabiscol E, Askjaer P, Cabello J, Miranda-Vizuete A.
Mol Neurobiol. 2018 Sep;55(9):7533-7552
THE SMALL GTPASE RAC1/CED-10 IS ESSENTIAL IN MAINTAINING DOPAMINERGIC NEURON FUNCTION AND SURVIVAL AGAINST ALPHA-SYNUCLEIN-INDUCED TOXICITY.
Kim H, Calatayud C, Guha S, Fernández-Carasa I, Berkowitz L, Carballo-Carbajal I, Ezquerra M, Fernández-Santiago R, Kapahi P, Raya Á, Miranda-Vizuete A, Lizcano JM, Vila M, Caldwell KA, Caldwell GA, Consiglio A, Dalfo E.
Acta Neuropathol. 2017 Dec;134(6):839-850.
THE NEUROPROTECTIVE TRANSCRIPTION FACTOR ATF5 IS DECREASED AND SEQUESTERED INTO POLYGLUTAMINE INCLUSIONS IN HUNTINGTON'S DISEASE.
Hernández IH, Torres-Peraza J, Santos-Galindo M, Ramos-Morón E, Fernández-Fernández MR, Pérez-Álvarez MJ, Miranda-Vizuete A, Lucas JJ.
Am J Hum Genet. 2016 Sep 1;99(3):695-703.
BIALLELIC VARIANTS IN UBA5 REVEAL THAT DISRUPTION OF THE UFM1 CASCADE CAN RESULT IN EARLY-ONSET ENCEPHALOPATHY.
Colin E, Daniel J, Ziegler A, Wakim J, Scrivo A, Haack TB, Khiati S, Denommé AS, Amati-Bonneau P, Charif M, Procaccio V, Reynier P, Aleck KA, Botto LD, Herper CL, Kaiser CS, Nabbout R, N'Guyen S, Mora-Lorca JA, Assmann B, Christ S, Meitinger T, Strom TM, Prokisch H; FREX Consortium, Miranda-Vizuete A, Hoffmann GF, Lenaers G, Bomont P, Liebau E, Bonneau D.
Biochim Biophys Acta. 2016 Sep;1864(9):1195-1205.
CAENORHABDITIS ELEGANS AGXT-1 IS A MITOCHONDRIAL AND TEMPERATURE-ADAPTED ORTHOLOG OF PEROXISOMAL HUMAN AGT1: NEW INSIGHTS INTO BETWEEN-SPECIES DIVERGENCE IN GLYOXYLATE METABOLISM.
Mesa-Torres N, Calvo AC, Oppici E, Titelbaum N, Montioli R, Miranda-Vizuete A, Cellini B, Salido E, Pey AL.
Free Radic Biol Med. 2016 Jul;96:446-61.
GLUTATHIONE REDUCTASE GSR-1 IS AN ESSENTIAL GENE REQUIRED FOR CAENORHABDITIS ELEGANS EARLY EMBRYONIC DEVELOPMENT.
Mora-Lorca JA, Sáenz-Narciso B, Gaffney CJ, Naranjo-Galindo FJ, Pedrajas JR, Guerrero-Gómez D, Dobrzynska A, Askjaer P, Szewczyk NJ, Cabello J, Miranda-Vizuete A.
Free Radic Biol Med. 2014 Mar;68:205-19.
FUNCTIONAL CHARACTERIZATION OF THIOREDOXIN 3 (TRX-3), A CAENORHABDITIS ELEGANS INTESTINE-SPECIFIC THIOREDOXIN.
Jiménez-Hidalgo M, Kurz CL, Pedrajas JR, Naranjo-Galindo FJ, González-Barrios M, Cabello J, Sáez AG, Lozano E, Button EL, Veal EA, Fierro-González JC, Swoboda P, Miranda-Vizuete A.
Antioxid Redox Signal. 2014 Jan 10;20(2):217-35.
PROTECTIVE ROLE OF DNJ-27/ERDJ5 IN CAENORHABDITIS ELEGANS MODELS OF HUMAN NEURODEGENERATIVE DISEASES.
Muñoz-Lobato F, Rodríguez-Palero MJ, Naranjo-Galindo FJ, Shephard F, Gaffney CJ, Szewczyk NJ, Hamamichi S, Caldwell KA, Caldwell GA, Link CD, Miranda-Vizuete A.
Antioxid Redox Signal. 2012 Jun 15;16(12):1384-400.
THE CHARACTERIZATION OF THE CAENORHABDITIS ELEGANS MITOCHONDRIAL THIOREDOXIN SYSTEM UNCOVERS AN UNEXPECTED PROTECTIVE ROLE OF THIOREDOXIN REDUCTASE 2 IN BETA-AMYLOID PEPTIDE TOXICITY.
Cacho-Valadez B, Muñoz-Lobato F, Pedrajas JR, Cabello J, Fierro-González JC, Navas P, Swoboda P, Link CD, Miranda-Vizuete A.
The True Boss
C. elegans joined the lab in 2005 after a successful career of more than 40 years at the front of Genetics and Cell Biology studies in many of the most renowned labs around the world. In our lab, it has made an outstanding contribution on the functional characterization of several members of the worm thioredoxin and glutaredoxin redox systems.
ANTONIO MIRANDA VIZUETE
The other boss
During his PhD studies he became familiar with the thioredoxin and glutaredoxin redox systems in bacteria. Next, at his postdoc, he participated on the characterization of the mammalian mitochondrial and the testis-specific thioredoxin systems. In 2002 he joined Peter Swoboda lab at Karolinska Institute to train on C. elegans and in 2005 he started his own lab in Seville to work on worm Redox Biology.
DAVID GUERRERO GÓMEZ
Technician and PhD. student
David graduated in Biology in 2006 and during several years he worked with C. elegans at Manuel Muñoz lab in Seville. In 2014 he joined our lab as technician and in 2016 he enroled the PhD. program working on the protective role of the glutathione system in worm models of neurodegenerative diseases.
CRISTINA ROMERO ARANDA
Cristina obtained her Biology Degree at Jaén University in 2018. She is currently performing her Master Thesis working on the redox regulation of the HLH-30 transcription factor.
ÁNGELA SANZO MACHUCA
Ángela is finishing her Biomedicine Degree at Seville University. She joined the lab in 2017 and since then she has been working on the identification of redox-independent functions of worm TRX-1.
ANA CEPERO MARTÍN
Ana is in her last year of Biomedicine Degree at Seville University. Together with her fellow Natalia (below), she will make her Final Degree Project working on the signaling pathways regulating TRX-1 expression upon starvation.
NATALIA CARRASQUILLA GARCÍA
Natalia is in her last year of Biomedicine Degree at Seville University. Together with her fellow Ana (above), she will make her Final Degree Project working on the signaling pathways regulating TRX-1 expression upon starvation.
FORMER LAB MEMBERS
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INTERESTED IN C. ELEGANS?
IF YOU WOULD LIKE TO WORK WITH C. ELEGANS IN YOUR MASTER PRACTICAL COURSE, PHD OR POSTDOC PLEASE SEND US AN EMAIL INCLUDING YOUR CV AND RESEARCH INTERESTS TO
Antonio Miranda-Vizuete, PhD
Redox Homeostasis Group
Instituto de Biomedicina de Sevilla (IBIS)
Hospital Universitario Virgen del Rocío
Avd. Antonio Maura Montaner s/n
41013 Seville, SPAIN