Examinando por Autor "Elorza, Alvaro A."
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Ítem Bile Acids Induce Alterations in Mitochondrial Function in Skeletal Muscle Fibers(MDPI, 2022-09) Abrigo, Johanna; Olguín, Hugo; Gutierrez, Danae; Tacchi, Franco; Arrese, Marco; Cabrera, Daniel; Valero Breton, Mayalen; Elorza, Alvaro A.; Simon, Felipe; Cabello Verrugio, ClaudioCholestatic chronic liver disease is characterized by developing sarcopenia and elevated serum levels of bile acids. Sarcopenia is a skeletal muscle disorder with the hallmarks of muscle weakness, muscle mass loss, and muscle strength decline. Our previous report demonstrated that deoxycholic acid (DCA) and cholic acid (CA), through the membrane receptor TGR5, induce a sarcopenia-like phenotype in myotubes and muscle fibers. The present study aimed to evaluate the impact of DCA and CA on mitochondrial mass and function in muscle fibers and the role of the TGR5 receptor. To this end, muscle fibers obtained from wild-type and TGR5−/− mice were incubated with DCA and CA. Our results indicated that DCA and CA decreased mitochondrial mass, DNA, and potential in a TGR5-dependent fashion. Furthermore, with TGR5 participation, DCA and CA also reduced the oxygen consumption rate and complexes I and II from the mitochondrial electron transport chain. In addition, DCA and CA generated more mitochondrial reactive oxygen species than the control, which were abolished in TGR5−/− mice muscle fibers. Our results indicate that DCA and CA induce mitochondrial dysfunction in muscle fibers through a TGR5-dependent mechanism. © 2022 by the authors.Ítem Biomarkers in Thyroid Cancer: Emerging Opportunities from Non-Coding RNAs and Mitochondrial Space(Multidisciplinary Digital Publishing Institute (MDPI), 2024-06) Cabané, Patricio; Correa, Claudio; Bode, Ignacio; Aguilar, Rodrigo; Elorza, Alvaro A.Thyroid cancer diagnosis primarily relies on imaging techniques and cytological analyses. In cases where the diagnosis is uncertain, the quantification of molecular markers has been incorporated after cytological examination. This approach helps physicians to make surgical decisions, estimate cancer aggressiveness, and monitor the response to treatments. Despite the availability of commercial molecular tests, their widespread use has been hindered in our experience due to cost constraints and variability between them. Thus, numerous groups are currently evaluating new molecular markers that ultimately will lead to improved diagnostic certainty, as well as better classification of prognosis and recurrence. In this review, we start reviewing the current preoperative testing methodologies, followed by a comprehensive review of emerging molecular markers. We focus on micro RNAs, long non-coding RNAs, and mitochondrial (mt) signatures, including mtDNA genes and circulating cell-free mtDNA. We envision that a robust set of molecular markers will complement the national and international clinical guides for proper assessment of the disease.Ítem Biosystem analysis of the hypoxia inducible domain family member 2A: Implications in cancer biology(MDPI AG, 2020-02) Salazar, Celia; Yañez, Osvaldo; Elorza, Alvaro A.; Cortes, Natalie; García-Beltrán, Olimpo; Tiznado, William; Ruiz, Lina MaríaThe expression of HIGD2A is dependent on oxygen levels, glucose concentration, and cell cycle progression. This gene encodes for protein HIG2A, found in mitochondria and the nucleus, promoting cell survival in hypoxic conditions. The genomic location of HIGD2A is in chromosome 5q35.2, where several chromosomal abnormalities are related to numerous cancers. The analysis of high definition expression profiles of HIGD2A suggests a role for HIG2A in cancer biology. Accordingly, the research objective was to perform a molecular biosystem analysis of HIGD2A aiming to discover HIG2A implications in cancer biology. For this purpose, public databases such as SWISS-MODEL protein structure homology-modelling server, Catalogue of Somatic Mutations in Cancer (COSMIC), Gene Expression Omnibus (GEO), MethHC: a database of DNA methylation and gene expression in human cancer, and microRNA-target interactions database (miRTarBase) were accessed. We also evaluated, by using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), the expression of Higd2a gene in healthy bone marrow-liver-spleen tissues of mice after quercetin (50 mg/kg) treatment. Thus, among the structural features of HIG2A protein that may participate in HIG2A translocation to the nucleus are an importin α-dependent nuclear localization signal (NLS), a motif of DNA binding residues and a probable SUMOylating residue. HIGD2A gene is not implicated in cancer via mutation. In addition, DNA methylation and mRNA expression of HIGD2A gene present significant alterations in several cancers; HIGD2A gene showed significant higher expression in Diffuse Large B-cell Lymphoma (DLBCL). Hypoxic tissues characterize the “bone marrow-liver-spleen” DLBCL type. The relative quantification, by using RT-qPCR, showed that Higd2a expression is higher in bone marrow than in the liver or spleen. In addition, it was observed that quercetin modulated the expression of Higd2a gene in mice. As an assembly factor of mitochondrial respirasomes, HIG2A might be unexpectedly involved in the change of cellular energetics happening in cancer. As a result, it is worth continuing to explore the role of HIGD2A in cancer biology. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.Ítem CD73 Ectonucleotidase Restrains CD8+ T Cell Metabolic Fitness and Anti-tumoral Activity(Frontiers Media S.A., 2021-02) Briceño, Pedro; Rivas-Yañez, Elizabeth; Rosemblatt, Mariana V.; Parra-Tello, Brian; Farías, Paula; Vargas, Leonardo; Simon, Valeska; Cárdenas, César; Lladser, Alvaro; Salazar-Onfray, Flavio; Elorza, Alvaro A.; Rosemblatt, Mario; Bono, María Rosa; Sauma, DanielaCD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells’ metabolic fitness. © Copyright © 2021 Briceño, Rivas-Yañez, Rosemblatt, Parra-Tello, Farías, Vargas, Simon, Cárdenas, Lladser, Salazar-Onfray, Elorza, Rosemblatt, Bono and Sauma.Ítem Cholic and deoxycholic acids induce mitochondrial dysfunction, impaired biogenesis and autophagic flux in skeletal muscle cells(BioMed Central Ltd, 2023-06) Abrigo, Johanna; Olguín, Hugo; Tacchi, Franco; Orozco-Aguilar, Josué; Valero-Breton, Mayalen; Soto, Jorge; Castro-Sepúlveda, Mauricio; Elorza, Alvaro A.; Simon, Felipe; Cabello-Verrugio, ClaudioBackground: Skeletal muscle is sensitive to bile acids (BA) because it expresses the TGR5 receptor for BA. Cholic (CA) and deoxycholic (DCA) acids induce a sarcopenia-like phenotype through TGR5-dependent mechanisms. Besides, a mouse model of cholestasis-induced sarcopenia was characterised by increased levels of serum BA and muscle weakness, alterations that are dependent on TGR5 expression. Mitochondrial alterations, such as decreased mitochondrial potential and oxygen consumption rate (OCR), increased mitochondrial reactive oxygen species (mtROS) and unbalanced biogenesis and mitophagy, have not been studied in BA-induced sarcopenia. Methods: We evaluated the effects of DCA and CA on mitochondrial alterations in C2C12 myotubes and a mouse model of cholestasis-induced sarcopenia. We measured mitochondrial mass by TOM20 levels and mitochondrial DNA; ultrastructural alterations by transmission electronic microscopy; mitochondrial biogenesis by PGC-1α plasmid reporter activity and protein levels by western blot analysis; mitophagy by the co-localisation of the MitoTracker and LysoTracker fluorescent probes; mitochondrial potential by detecting the TMRE probe signal; protein levels of OXPHOS complexes and LC3B by western blot analysis; OCR by Seahorse measures; and mtROS by MitoSOX probe signals. Results: DCA and CA caused a reduction in mitochondrial mass and decreased mitochondrial biogenesis. Interestingly, DCA and CA increased LC3II/LC3I ratio and decreased autophagic flux concordant with raised mitophagosome-like structures. In addition, DCA and CA decreased mitochondrial potential and reduced protein levels in OXPHOS complexes I and II. The results also demonstrated that DCA and CA decreased basal, ATP-linked, FCCP-induced maximal respiration and spare OCR. DCA and CA also reduced the number of cristae. In addition, DCA and CA increased the mtROS. In mice with cholestasis-induced sarcopenia, TOM20, OXPHOS complexes I, II and III, and OCR were diminished. Interestingly, the OCR and OXPHOS complexes were correlated with muscle strength and bile acid levels. Conclusion: Our results showed that DCA and CA decreased mitochondrial mass, possibly by reducing mitochondrial biogenesis, which affects mitochondrial function, thereby altering potential OCR and mtROS generation. Some mitochondrial alterations were also observed in a mouse model of cholestasis-induced sarcopenia characterised by increased levels of BA, such as DCA and CA. © 2023, The Author(s).Ítem Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells(Metallomics, 2019-02) Jensen, Erik L.; Gonzalez-Ibanez, Alvaro M.; Mendoza, Pierina; Ruiz, Lina M.; Riedel, Claudia A.; Simon, Felipe; Schuringa, Jan J.; Elorza, Alvaro A.The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine-a copper chelator-showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.Ítem Excess iodide induces an acute inhibition of the sodium/iodide symporter in thyroid male rat cells by increasing reactive oxygen species(Endocrine Society, 2015-04) Arriagada, Alejandro A.; Albornoz, Eduardo; Opazo, Ma. Cecilia; Becerra, Alvaro; Vidal, Gonzalo; Fardella, Carlos; Michea, Luis; Carrasco, Nancy; Simon, Felipe; Elorza, Alvaro A.; Bueno, Susan M.; Kalergis, Alexis M.Na+/I− symporter (NIS) mediates iodide (I−) uptake in the thyroid gland, the first and rate-limiting step in the biosynthesis of the thyroid hormones. The expression and function of NIS in thyroid cells is mainly regulated by TSH and by the intracellular concentration of I−. High doses of I− for 1 or 2 days inhibit the synthesis of thyroid hormones, a process known as the Wolff-Chaikoff effect. The cellular mechanisms responsible for this physiological response are mediated in part by the inhibition of I− uptake through a reduction of NIS expression. Here we show that inhibition of I− uptake occurs as early as 2 hours or 5 hours after exposure to excess I− in FRTL-5 cells and the rat thyroid gland, respectively. Inhibition of I− uptake was not due to reduced NIS expression or altered localization in thyroid cells. We observed that incubation of FRTL-5 cells with excess I− for 2 hours increased H2O2 generation. Furthermore, the inhibitory effect of excess I− on NIS-mediated I− transport could be recapitulated by H2O2 and reverted by reactive derived oxygen species scavengers. The data shown here support the notion that excess I− inhibits NIS at the cell surface at early times by means of a posttranslational mechanism that involves reactive derived oxygen species.Ítem Quercetin Affects Erythropoiesis and Heart Mitochondrial Function in Mice(Hindawi Publishing Corporation, 2015) Ruiz, Lina M.; Salazar, Celia; Jensen, Erik; Ruiz, Paula A.; Tiznado, William; Quintanilla, Rodrigo A.; Barreto, Marlen; Elorza, Alvaro A.Quercetin, a dietary flavonoid used as a food supplement, showed powerful antioxidant effects in different cellular models. However, recent in vitro and in vivo studies in mammals have suggested a prooxidant effect of quercetin and described an interaction with mitochondria causing an increase in O2- production, a decrease in ATP levels, and impairment of respiratory chain in liver tissue. Therefore, because of its dual actions, we studied the effect of quercetin in vivo to analyze heart mitochondrial function and erythropoiesis. Mice were injected with 50 mg/kg of quercetin for 15 days. Treatment with quercetin decreased body weight, serum insulin, and ceruloplasmin levels as compared with untreated mice. Along with an impaired antioxidant capacity in plasma, quercetin-treated mice showed a significant delay on erythropoiesis progression. Heart mitochondrial function was also impaired displaying more protein oxidation and less activity for IV, respectively, than no-treated mice. In addition, a significant reduction in the protein expression levels of Mitofusin 2 and Voltage-Dependent Anion Carrier was observed. All these results suggest that quercetin affects erythropoiesis and mitochondrial function and then its potential use as a dietary supplement should be reexamined. © 2015 Lina M. Ruiz et al.Ítem Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling(Frontiers Research Foundation, 2015-06) Rojas, Fabiola; Gonzalez, David; Cortes, Nicole; Ampuero, Estibaliz; Hernández, Diego E; Fritz, Elsa; Abarzua, Sebastián; Martinez, Alexis; Elorza, Alvaro A.; Alvarez, Alejandra; Court, Felipe; Van Zundert, BrigitteAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1G93A(ACM-hSOD1G93A) quickly enhances Nav channel- mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1G93A, but not ACM-hSOD1WT, increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1G93A-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1G86Ror TDP43A315T. We further find that co-application of ACM-SOD1G93Awith blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1G93Ainduces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death. © 2015 Rojas,Gonzalez,CortesÍtem Role of oxidative stress as key regulator of muscle wasting during cachexia(Hindawi Limited, 2018) Abrigo, Johanna; Elorza, Alvaro A.; Riedel, Claudia A.; Vilos, Cristian; Simon, Felipe; Cabrera, Daniel; Estrada, LisbellSkeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia. Copyright © 2018 Johanna Ábrigo et al. Reaxys Chemistry database informationLearn about Reaxys chemistry database informationÍtem Wnt signaling induces transcription, spatial proximity, and translocation of fusion gene partners in human hematopoietic cells(American Society of Hematology, 2015-10) Ugarte, Giorgia D.; Vargas, Macarena F.; Medina, Matías A.; León, Pablo; Necuñir, David; Elorza, Alvaro A.; Gutiérrez, Soraya E.; Moon, Randall T.; Loyola, Alejandra; De Ferrari, Giancarlo V.Chromosomal translocations are frequently associated with a wide variety of cancers, particularly hematologic malignancies. A recurrent chromosomal abnormality in acute myeloid leukemia is the reciprocal translocation t(8;21) that fuses RUNX1 and ETO genes. We report here that Wnt/β-catenin signaling increases the expression of ETO and RUNX1 genes in human hematopoietic progenitors. We found that β-catenin is rapidly recruited into RNA polymerase II transcription factories (RNAPII-Ser5) and that ETO and RUNX1 genes are brought into close spatial proximity upon Wnt3a induction. Notably, long-term treatment of cells with Wnt3a induces the generation a frequent RUNX1-ETO translocation event. Thus, Wnt/β-catenin signaling induces transcription and translocation of RUNX1 and ETO fusion gene partners, opening a novel window to understand the onset/development of leukemia. © 2015 by The American Society of Hematology.