Person: Latorre-Pellicer, Ana
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Ana
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Latorre-Pellicer
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CNIC
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Publication Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome.(Nature Publishing Group, 2021-07-27) Garcia, Patricia; Fernandez-Hernandez, Rita; Cuadrado, Ana; Coca, Ignacio; Gomez, Antonio; Maqueda, Maria; Latorre-Pellicer, Ana; Puisac, Beatriz; Ramos, Feliciano J; Sandoval, Juan; Esteller, Manel; Mosquera, Jose Luis; Rodriguez, Jairo; Pié, J; Queralt, Ethel; Losada, Ana; Ministerio de Economía, Industria y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundación La Marató TV3; Government of Catalonia (España); Instituto de Salud Carlos IIICornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF.Publication Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy(Cell Press, 2019-12-03) Latorre-Pellicer, Ana; Lechuga-Vieco, Ana V.; Johnston, Iain G; Hämäläinen, Riikka H; Pellico, Juan; Justo-Mendez, Raquel; Fernandez-Toro, Jose Maria; Claveria, Cristina; Guaras, Adela; Sierra, Rocio; Llop, Jordi; Torres, Miguel; Criado-Rodriguez, Luis M.; Suomalainen, Anu; Jones, Nick S; Ruiz-Cabello, Jesus; Enriquez, Jose Antonio; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Fundación ProCNIC; Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Comisión EuropeamtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission.Publication Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics.(American Association for the Advancement of Science (AAAS), 2020-07) Lechuga-Vieco, Ana V.; Latorre-Pellicer, Ana; Johnston, Iain G; Prota, Gennaro; Gileadi, Uzi; Justo-Mendez, Raquel; Acin-Perez, Rebeca; Martínez-de-Mena, Raquel; Fernandez-Toro, Jose Maria; Jimenez-Blasco, Daniel; Mora, Alfonso; Nicolas-Avila, Jose A.; Santiago, Demetrio J; Priori, Silvia G.; Bolaños, Juan Pedro; Sabio, Guadalupe; Criado-Rodriguez, Luis M.; Ruiz-Cabello, Jesus; Cerundolo, Vincenzo; Jones, Nick S; Enriquez, Jose Antonio; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Comunidad de Madrid (España); Unión Europea. Comisión Europea; Centro de Investigación Biomedica en Red - CIBER; Medical Research Council (Reino Unido); Cancer Research UK (Reino Unido); Unión Europea. Comisión Europea. European Research Council (ERC); Fundación ProCNIC; Fundación BBVAHeteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.Publication Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.(American Heart Association (AHA), 2022-04-05) Lechuga-Vieco, Ana Victoria; Latorre-Pellicer, Ana; Calvo, Enrique; Torroja, Carlos; Pellico, Juan; Acin-Perez, Rebeca; García-Gil, María Luisa; Santos, Arnoldo; Bagwan, Navratan; Bonzon-Kulichenko, Elena; Magni, Ricardo; Benito, Marina; Justo-Méndez, Raquel; Simon, Anna Katharina; Sanchez-Cabo, Fatima; Vazquez, Jesus; Ruíz-Cabello, Jesús; Enriquez, Jose Antonio; Ministerio de Ciencia e Innovación (España); European Molecular Biology Organization; Humand Frontier Science Program; Ministerio de Economía, Industria y Competitividad (España); Programa Red Guipuzcoana de Ciencia, Tecnología e Información; Basque Government (España); ELKARTEK Program; Fundación BBVA; Ministerio de Ciencia e Innovación. Unidades de Excelencia María de Maeztu. (España); Unión Europea. Comisión Europea. H2020; Marie Curie; Fundación La Marató TV3; Fundación La Caixa; Instituto de Salud Carlos III; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Agencia Estatal de Investigación (España)In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.Publication Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts(Nature Publishing Group, 2018) Torralba, Daniel; Baixauli, Francesc; Villarroya-Beltri, Carolina; Fernandez-Delgado, Irene; Latorre-Pellicer, Ana; Acin-Perez, Rebeca; Martin-Cofreces, Noa B.; Jaso-Tamame, Angel Luis; Iborra, Salvador; Jorge, Inmaculada; Gonzalez-Aseguinolaza, Gloria; Garaude, Johan; Vicente-Manzanares, Miguel; Enriquez, Jose Antonio; Mittelbrunn, Maria; Sanchez-Madrid, Francisco; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España); Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Comisión Europea; Instituto de Salud Carlos III; Fundación ProCNIC; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Interaction of T cell with antigen-bearing dendritic cells (DC) results in T cell activation, but whether this interaction has physiological consequences on DC function is largely unexplored. Here we show that when antigen-bearing DCs contact T cells, DCs initiate antipathogenic programs. Signals of this interaction are transmitted from the T cell to the DC, through extracellular vesicles (EV) that contain genomic and mitochondrial DNA, to induce antiviral responses via the cGAS/STING cytosolic DNA-sensing pathway and expression of IRF3-dependent interferon regulated genes. Moreover, EV-treated DCs are more resistant to subsequent viral infections. In summary, our results show that T cells prime DCs through the transfer of exosomal DNA, supporting a specific role for antigen-dependent contacts in conferring protection to DCs against pathogen infection. The reciprocal communication between innate and adaptive immune cells thus allow efficacious responses to unknown threats.Publication Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.(Elsevier, 2022-08) Gonzalez-Franquesa, Alba; Gama-Perez, Pau; Kulis, Marta; Szczepanowska, Karolina; Dahdah, Norma; Moreno-Gomez, Sonia; Latorre-Pellicer, Ana; Fernández-Ruiz, Rebeca; Aguilar-Mogas, Antoni; Hoffman, Anne; Monelli, Erika; Samino, Sara; Miró-Blanch, Joan; Oemer, Gregor; Duran, Xavier; Sanchez-Rebordelo, Estrella; Schneeberger, Marc; Obach, Merce; Montane, Joel; Castellano, Giancarlo; Chapaprieta, Vicente; Sun, Wenfei; Navarro, Lourdes; Prieto, Ignacio; Castaño, Carlos; Novials, Anna; Gomis, Ramon; Monsalve, Maria; Claret, Marc; Graupera, Mariona; Soria, Guadalupe; Wolfrum, Christian; Vendrell, Joan; Fernández-Veledo, Sonia; Enriquez, Jose Antonio; Carracedo, Angel; Perales, José Carlos; Nogueiras, Rubén; Herrero, Laura; Trifunovic, Aleksandra; Keller, Markus A; Yanes, Oscar; Sales-Pardo, Marta; Guimerà, Roger; Blüher, Matthias; Martín-Subero, José Ignacio; Garcia-Roves, Pablo M; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Government of Catalonia (España); Ministerio de Economía, Innovación y Competitividad (España); Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea. H2020; Centro de Investigación Biomédica en Red - CIBEROBN (Fisiopatología de la Obesidad y Nutrición); Fundación La Marató TV3; Novo Nordisk Foundation; Fundación Alicia KoplowitzMetabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.Publication Comprehensive Quantification of the Modified Proteome Reveals Oxidative Heart Damage in Mitochondrial Heteroplasmy(Cell Press, 2018) Bagwan, Navratan; Bonzon-Kulichenko, Elena; Calvo, Enrique; Lechuga-Vieco, Ana V.; Michalakopoulos, Spiros; Trevisan-Herraz, Marco; Ezkurdia, Iakes; Rodriguez, Jose Manuel; Magni, Ricardo; Latorre-Pellicer, Ana; Enriquez, Jose Antonio; Vazquez, Jesus; Ministerio de Economía y Competitividad (España); Fundación La Marató TV3; Unión Europea. Comisión Europea; Instituto de Salud Carlos III; Fundación ProCNICPost-translational modifications hugely increase the functional diversity of proteomes. Recent algorithms based on ultratolerant database searching are forging a path to unbiased analysis of peptide modifications by shotgun mass spectrometry. However, these approaches identify only one-half of the modified forms potentially detectable and do not map the modified residue. Moreover, tools for the quantitative analysis of peptide modifications are currently lacking. Here, we present a suite of algorithms that allows comprehensive identification of detectable modifications, pinpoints the modified residues, and enables their quantitative analysis through an integrated statistical model. These developments were used to characterize the impact of mitochondrial heteroplasmy on the proteome and on the modified peptidome in several tissues from 12-week-old mice. Our results reveal that heteroplasmy mainly affects cardiac tissue, inducing oxidative damage to proteins of the oxidative phosphorylation system, and provide a molecular mechanism explaining the structural and functional alterations produced in heart mitochondria.