143 results on '"Goikoetxea-Usandizaga, Naroa"'
Search Results
2. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer
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Lachiondo-Ortega, Sofia, Rejano-Gordillo, Claudia M., Simon, Jorge, Lopitz-Otsoa, Fernando, C. Delgado, Teresa, Mazan-Mamczarz, Krystyna, Goikoetxea-Usandizaga, Naroa, Zapata-Pavas, L. Estefanía, García-del Río, Ana, Guerra, Pietro, Peña-Sanfélix, Patricia, Hermán-Sánchez, Natalia, Al-Abdulla, Ruba, Fernandez-Rodríguez, Carmen, Azkargorta, Mikel, Velázquez-Cruz, Alejandro, Guyon, Joris, Martín, César, Zalamea, Juan Diego, Egia-Mendikute, Leire, Sanz-Parra, Arantza, Serrano-Maciá, Marina, González-Recio, Irene, Gonzalez-Lopez, Monika, Martínez-Cruz, Luis Alfonso, Pontisso, Patrizia, Aransay, Ana M., Barrio, Rosa, Sutherland, James D., Abrescia, Nicola G.A., Elortza, Félix, Lujambio, Amaia, Banales, Jesus M., Luque, Raúl M., Gahete, Manuel D., Palazón, Asís, Avila, Matias A., G. Marin, Jose J., De, Supriyo, Daubon, Thomas, Díaz-Quintana, Antonio, Díaz-Moreno, Irene, Gorospe, Myriam, Rodríguez, Manuel S., and Martínez-Chantar, María Luz
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- 2024
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3. Anti-miR-873-5p improves alcohol-related liver disease by enhancing hepatic deacetylation via SIRT1
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Rodríguez-Agudo, Rubén, González-Recio, Irene, Serrano-Maciá, Marina, Bravo, Miren, Petrov, Petar, Blaya, Delia, Herranz, Jose María, Mercado-Gómez, María, Rejano-Gordillo, Claudia María, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Azkargorta, Mikel, Van Liempd, Sebastiaan Martijn, Martinez-Cruz, Luis Alfonso, Simão, A.L., Elortza, Félix, Martín, César, Nevzorova, Yulia A., Cubero, Francisco Javier, Delgado, Teresa C., Argemi, Josepmaria, Bataller, Ramón, Schoonjans, Kristina, Banales, Jesús M., Castro, Rui E., Sancho-Bru, Pau, Avila, Matías A., Julve, Josep, Jover, Ramiro, Mabe, Jon, Simon, Jorge, Goikoetxea-Usandizaga, Naroa, and Martínez-Chantar, María L.
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- 2024
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4. Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity.
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Fernández-Tussy, Pablo, Rodríguez-Agudo, Rubén, Fernández-Ramos, David, Barbier-Torres, Lucía, Zubiete-Franco, Imanol, Davalillo, Sergio López de, Herraez, Elisa, Goikoetxea-Usandizaga, Naroa, Lachiondo-Ortega, Sofia, Simón, Jorge, Lopitz-Otsoa, Fernando, Juan, Virginia Gutiérrez-de, McCain, Misti V, Perugorria, Maria J, Mabe, Jon, Navasa, Nicolás, Rodrigues, Cecilia MP, Fabregat, Isabel, Boix, Loreto, Sapena, Victor, Anguita, Juan, Lu, Shelly C, Mato, José M, Banales, Jesus M, Villa, Erica, Reeves, Helen L, Bruix, Jordi, Reig, Maria, Marin, Jose JG, Delgado, Teresa C, and Martínez-Chantar, María L
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Biochemistry and Cell Biology ,Oncology and Carcinogenesis - Abstract
Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 and n = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.
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- 2021
5. Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting
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Capelo-Diz, Alba, Lachiondo-Ortega, Sofía, Fernández-Ramos, David, Cañas-Martín, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, González-Rellan, Maria J., Mosca, Laura, Blazquez-Vicens, Joan, Tinahones-Ruano, Alberto, Fondevila, Marcos F., Buyan, Mason, Delgado, Teresa C., Gutierrez de Juan, Virginia, Ayuso-García, Paula, Sánchez-Rueda, Alejandro, Velasco-Avilés, Sergio, Fernández-Susavila, Héctor, Riobello-Suárez, Cristina, Dziechciarz, Bartlomiej, Montiel-Duarte, Cristina, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Bilbao-García, Jon, Bernardo-Seisdedos, Ganeko, Senra, Ana, Soriano-Navarro, Mario, Millet, Oscar, Díaz-Lagares, Ángel, Crujeiras, Ana B., Bao-Caamano, Aida, Cabrera, Diana, van Liempd, Sebastiaan, Tamayo-Caro, Miguel, Borzacchiello, Luigi, Gomez-Santos, Beatriz, Buqué, Xabier, Sáenz de Urturi, Diego, González-Romero, Francisco, Simon, Jorge, Rodríguez-Agudo, Rubén, Ruiz, Asier, Matute, Carlos, Beiroa, Daniel, Falcon-Perez, Juan M., Aspichueta, Patricia, Rodríguez-Cuesta, Juan, Porcelli, Marina, Pajares, María A., Ameneiro, Cristina, Fidalgo, Miguel, Aransay, Ana M., Lama-Díaz, Tomas, Blanco, Miguel G., López, Miguel, Villa-Bellosta, Ricardo, Müller, Timo D., Nogueiras, Rubén, Woodhoo, Ashwin, Martínez-Chantar, María Luz, and Varela-Rey, Marta
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- 2023
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6. Magnesium and Liver Metabolism Through the Lifespan
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Bravo, Miren, Simón, Jorge, González-Recio, Irene, Martinez-Cruz, Luis Alfonso, Goikoetxea-Usandizaga, Naroa, and Martínez-Chantar, María Luz
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- 2023
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7. Targeting Hepatic Glutaminase 1 Ameliorates Non-alcoholic Steatohepatitis by Restoring Very-Low-Density Lipoprotein Triglyceride Assembly
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Simon, Jorge, Nuñez-García, Maitane, Fernández-Tussy, Pablo, Barbier-Torres, Lucía, Fernández-Ramos, David, Gómez-Santos, Beatriz, Buqué, Xabier, Lopitz-Otsoa, Fernando, Goikoetxea-Usandizaga, Naroa, Serrano-Macia, Marina, Rodriguez-Agudo, Rubén, Bizkarguenaga, Maider, Zubiete-Franco, Imanol, Gutiérrez-de Juan, Virginia, Cabrera, Diana, Alonso, Cristina, Iruzubieta, Paula, Romero-Gomez, Manuel, van Liempd, Sebastiaan, Castro, Azucena, Nogueiras, Ruben, Varela-Rey, Marta, Falcón-Pérez, Juan Manuel, Villa, Erica, Crespo, Javier, Lu, Shelly C, Mato, Jose M, Aspichueta, Patricia, Delgado, Teresa C, and Martínez-Chantar, María Luz
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Biochemistry and Cell Biology ,Biological Sciences ,Hepatitis ,Chronic Liver Disease and Cirrhosis ,Liver Disease ,Nutrition ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Adult ,Animals ,Choline ,Disease Models ,Animal ,Female ,Glutaminase ,Hepatocytes ,Humans ,Lipid Metabolism ,Lipoproteins ,VLDL ,Liver ,Male ,Methionine ,Mice ,Inbred C57BL ,Non-alcoholic Fatty Liver Disease ,Oxidative Stress ,Phospholipids ,Triglycerides ,GLS1 ,GLS2 ,NAFLD ,NASH ,TCA cycle ,VLDL ,folate cycle ,glutaminase ,methionine cycle ,phospholipids ,Medical Biochemistry and Metabolomics ,Endocrinology & Metabolism ,Biochemistry and cell biology ,Medical biochemistry and metabolomics - Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform (GLS1) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse primary hepatocytes, in human hepatocyte cell lines, and in NASH mouse livers. We suggest that under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprogramming of serine metabolism, wherein serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. The restored methionine cycle can induce phosphatidylcholine synthesis from the phosphatidylethanolamine N-methyltransferase-mediated and CDP-choline pathways as well as by base-exchange reactions between phospholipids, thereby restoring hepatic phosphatidylcholine content and very-low-density lipoprotein export. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.
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- 2020
8. FRI-466-YI Implications and therapeutic potential of neddylation for pediatric liver cancer: hepatoblastoma
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Zapata-Pavas, Leidy Estefanía, primary, Serrano-Macía, Marina, additional, Rodrigo, Miguel Angel Merlos, additional, Peña-Sanfelix, Patricia, additional, Gil-Pitarch, Claudia, additional, Goikoetxea-Usandizaga, Naroa, additional, Michalkova, Hana, additional, Heger, Zbynek, additional, del Río-Álvarez, Alvaro, additional, Royo, Laura, additional, Rejano-Gordillo, Claudia M., additional, Barrenechea-Barrenechea, Jon Ander, additional, Mercado-Gómez, Maria, additional, Lachiondo-Ortega, Sofia, additional, Delgado, Teresa C., additional, Xirodimas, Dimitris, additional, Marin, Jose J.G., additional, Fernandez-Barrena, Maite G., additional, Avila, Matías A., additional, Armengol, Carolina, additional, and Martínez-Chantar, María Luz, additional
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- 2024
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9. The spike of SARS-CoV-2 promotes metabolic rewiring in hepatocytes
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Mercado-Gómez, Maria, Prieto-Fernández, Endika, Goikoetxea-Usandizaga, Naroa, Vila-Vecilla, Laura, Azkargorta, Mikel, Bravo, Miren, Serrano-Maciá, Marina, Egia-Mendikute, Leire, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofia, Lee, So Young, Eguileor Giné, Alvaro, Gil-Pitarch, Clàudia, González-Recio, Irene, Simón, Jorge, Petrov, Petar, Jover, Ramiro, Martínez-Cruz, Luis Alfonso, Ereño-Orbea, June, Delgado, Teresa Cardoso, Elortza, Felix, Jiménez-Barbero, Jesús, Nogueiras, Ruben, Prevot, Vincent, Palazon, Asis, and Martínez-Chantar, María L.
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- 2022
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10. Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients
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Serrano-Maciá, Marina, Lachiondo-Ortega, Sofia, Iruzubieta, Paula, Goikoetxea-Usandizaga, Naroa, Bosch, Alexandre, Egia-Mendikute, Leire, Jiménez-Lasheras, Borja, Azkargorta, Mikel, Elortza, Félix, Martinez-Redondo, Diana, Castro, Begoña, Lozano, Juan J., Nogueiras, Ruben, Irure-Ventura, Juan, Crespo, Javier, Palazón, Asís, Fariñas, María Carmen, Delgado, Teresa C., López-Hoyos, Marcos, and Martínez-Chantar, Maria L.
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- 2022
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11. Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis
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Sáenz de Urturi, Diego, Buqué, Xabier, Porteiro, Begoña, Folgueira, Cintia, Mora, Alfonso, Delgado, Teresa C., Prieto-Fernández, Endika, Olaizola, Paula, Gómez-Santos, Beatriz, Apodaka-Biguri, Maider, González-Romero, Francisco, Nieva-Zuluaga, Ane, Ruiz de Gauna, Mikel, Goikoetxea-Usandizaga, Naroa, García-Rodríguez, Juan Luis, Gutierrez de Juan, Virginia, Aurrekoetxea, Igor, Montalvo-Romeral, Valle, Novoa, Eva M., Martín-Guerrero, Idoia, Varela-Rey, Marta, Bhanot, Sanjay, Lee, Richard, Banales, Jesus M., Syn, Wing-Kin, Sabio, Guadalupe, Martínez-Chantar, María L., Nogueiras, Rubén, and Aspichueta, Patricia
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- 2022
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12. Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage
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González-Recio, Irene, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Mercado-Gómez, Maria, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Fernández-Rodríguez, Carmen, Castellana, Donatello, Latasa, Maria U., Abecia, Leticia, Anguita, Juan, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Avila, Matías A., Martín, César, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raul J., Lucena, M. Isabel, Buccella, Daniela, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, Maria L
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- 2022
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13. Novel Emerging Mechanisms in Acetaminophen (APAP) Hepatotoxicity.
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Hionides‐Gutierrez, Alejandro, Goikoetxea‐Usandizaga, Naroa, Sanz‐García, Carlos, Martínez‐Chantar, María L., and Cubero, Francisco Javier
- Abstract
ABSTRACT Background Aims Materials & Methods Results Discussion & Conclusion Drug‐induced liver injury represents a critical public health issue, marked by unpredictable and potentially severe adverse reactions to medications, herbal products or dietary supplements.Acetaminophen is notably a leading cause of hepatotoxicity, impacting over one million individuals worldwide.Extensive research has elucidated the intricate mechanisms driving APAP‐induced liver injury, emphasising the significant roles of endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction and cell death.These insights pave the way for innovative therapeutic strategies, including the use of magnesium, bile acids, microbiota modulation and mesenchymal stem cells.This review explores into these pathological mechanisms, proposing viable therapeutic interventions for patients suffering from APAP‐induced liver injury. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis
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Serrano-Maciá, Marina, Simón, Jorge, González-Rellan, Maria J., Azkargorta, Mikel, Goikoetxea-Usandizaga, Naroa, Lopitz-Otsoa, Fernando, De Urturi, Diego Saenz, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofia, Mercado-Gomez, Maria, Gutiérrez de Juan, Virginia, Bizkarguenaga, Maider, Fernández-Ramos, David, Buque, Xabier, Baselli, Guido A., Valenti, Luca V.C., Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Banales, Jesus M., Avila, Matias A., Marin, Jose J.G., Aspichueta, Patricia, Sutherland, James, Barrio, Rosa, Mayor, Ugo, Elortza, Félix, Xirodimas, Dimitris P., Nogueiras, Rubén, Delgado, Teresa C., and Martínez-Chantar, María Luz
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- 2021
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15. Boosting mitochondria activity by silencing MCJ overcomes cholestasis-induced liver injury
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Iruzubieta, Paula, Goikoetxea-Usandizaga, Naroa, Barbier-Torres, Lucía, Serrano-Maciá, Marina, Fernández-Ramos, David, Fernández-Tussy, Pablo, Gutiérrez-de-Juan, Virginia, Lachiondo-Ortega, Sofia, Simon, Jorge, Bravo, Miren, Lopitz-Otsoa, Fernando, Robles, Mercedes, Ferre-Aracil, Carlos, Varela-Rey, Marta, Elguezabal, Natalia, Calleja, José Luis, Lu, Shelly C., Milkiewicz, Malgorzata, Milkiewicz, Piotr, Anguita, Juan, Monte, María J., Marin, José J.G., López-Hoyos, Marcos, Delgado, Teresa C., Rincón, Mercedes, Crespo, Javier, and Martínez-Chantar, María Luz
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- 2021
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16. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer
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Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, Instituto de Salud Carlos III, Fundación la Caixa, Consejo Nacional de Ciencia y Tecnología (CONACYT). México, European Union (UE), National Institutes of Health. United States, Junta de Andalucía, Junta de Castilla-León, Gobierno de Navarra, Gobierno Vasco, National Cancer Institute (NCI), NIH. United States, Lachiondo Ortega, Sofia, Rejano Gordillo, Claudia M., Simon, Jorge, Lopitz Otsoa, Fernando, C. Delgado, Teresa, Mazan Mamczarz, Krystyna, Goikoetxea Usandizaga, Naroa, Velázquez Cruz, Alejandro, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, Martínez-Chantar, María Luz, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, Instituto de Salud Carlos III, Fundación la Caixa, Consejo Nacional de Ciencia y Tecnología (CONACYT). México, European Union (UE), National Institutes of Health. United States, Junta de Andalucía, Junta de Castilla-León, Gobierno de Navarra, Gobierno Vasco, National Cancer Institute (NCI), NIH. United States, Lachiondo Ortega, Sofia, Rejano Gordillo, Claudia M., Simon, Jorge, Lopitz Otsoa, Fernando, C. Delgado, Teresa, Mazan Mamczarz, Krystyna, Goikoetxea Usandizaga, Naroa, Velázquez Cruz, Alejandro, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, and Martínez-Chantar, María Luz
- Abstract
The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.
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- 2024
17. Potential Role of the mTORC1-PGC1α-PPARα Axis under Type-II Diabetes and Hypertension in the Human Heart
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Hang, Tianyu, primary, Lumpuy-Castillo, Jairo, additional, Goikoetxea-Usandizaga, Naroa, additional, Azkargorta, Mikel, additional, Aldámiz, Gonzalo, additional, Martínez-Milla, Juan, additional, Forteza, Alberto, additional, Cortina, José M., additional, Egido, Jesús, additional, Elortza, Félix, additional, Martínez-Chantar, Malu, additional, Tuñón, José, additional, and Lorenzo, Óscar, additional
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- 2023
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18. Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression
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Juárez‐Fernández, María, primary, Goikoetxea‐Usandizaga, Naroa, additional, Porras, David, additional, García‐Mediavilla, María Victoria, additional, Bravo, Miren, additional, Serrano‐Maciá, Marina, additional, Simón, Jorge, additional, Delgado, Teresa C., additional, Lachiondo‐Ortega, Sofía, additional, Martínez‐Flórez, Susana, additional, Lorenzo, Óscar, additional, Rincón, Mercedes, additional, Varela‐Rey, Marta, additional, Abecia, Leticia, additional, Rodríguez, Héctor, additional, Anguita, Juan, additional, Nistal, Esther, additional, Martínez‐Chantar, María Luz, additional, and Sánchez‐Campos, Sonia, additional
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- 2023
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19. Data from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary
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- 2023
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20. Supplementary Information from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary
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- 2023
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21. Supplementary Table 1 from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary
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- 2023
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22. Supplementary Data from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary
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- 2023
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23. Supplementary Table 2 from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary
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- 2023
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24. Supplementary Figures from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary
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- 2023
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25. Supplementary Table 3 from E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
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González-Romero, Francisco, primary, Mestre, Daniela, primary, Aurrekoetxea, Igor, primary, O'Rourke, Colm J., primary, Andersen, Jesper B., primary, Woodhoo, Ashwin, primary, Tamayo-Caro, Miguel, primary, Varela-Rey, Marta, primary, Palomo-Irigoyen, Marta, primary, Gómez-Santos, Beatriz, primary, de Urturi, Diego Sáenz, primary, Núñez-García, Maitane, primary, García-Rodríguez, Juan L., primary, Fernández-Ares, Larraitz, primary, Buqué, Xabier, primary, Iglesias-Ara, Ainhoa, primary, Bernales, Irantzu, primary, De Juan, Virginia Gutierrez, primary, Delgado, Teresa C., primary, Goikoetxea-Usandizaga, Naroa, primary, Lee, Richard, primary, Bhanot, Sanjay, primary, Delgado, Igotz, primary, Perugorria, Maria J., primary, Errazti, Gaizka, primary, Mosteiro, Lorena, primary, Gaztambide, Sonia, primary, Martinez de la Piscina, Idoia, primary, Iruzubieta, Paula, primary, Crespo, Javier, primary, Banales, Jesus M., primary, Martínez-Chantar, Maria L., primary, Castaño, Luis, primary, Zubiaga, Ana M., primary, and Aspichueta, Patricia, primary
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- 2023
- Full Text
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26. The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent
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Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Eusko Jaurlaritza, National Institutes of Health (US), National Institute on Alcohol Abuse and Alcoholism (US), Junta de Castilla y León, Junta de Andalucía, European Research Council, German Research Foundation, Ministerio de Educación, Cultura y Deporte (España), Fundació La Marató de TV3, Universidad del País Vasco, Asociación Española Contra el Cáncer, Fundación la Caixa, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Goikoetxea-Usandizaga, Naroa, Bravo, Miren, Egia-Mendikute, Leire, Abecia, Leticia, Serrano-Maciá, Marina, Urdinguio, Rocío G., Clos-García, Marc, Rodríguez-Agudo, Rubén, Araujo-Legido, Raquel, López-Bermudo, Lucía, Delgado, Teresa C., Lachiondo-Ortega, Sofía, González-Recio, Irene, Gil-Pitarch, Clàudia, Peña-Cearra, Ainize, Simón, Jorge, Benedé-Ubieto, Raquel, Ariño, Silvia, Herranz, Jose M., Azkargorta, Mikel, Salazar-Bermeo, Julio, Martí, Nuria, Varela-Rey, Marta, Falcón-Pérez, Juan M., Lorenzo, Óscar, Nogueiras, Rubén, Elortza, Félix, Nevzorova, Yulia, Cubero, Francisco J., Saura, Domingo, Martínez-Cruz, Luis Alfonso, Sabio, Guadalupe, Palazón, Asís, Sancho-Bru, Pau, Elguezabal, Natalia, Fraga, Mario F., Ávila, Matías A., Bataller, Ramón, Marín, José J. G., Martín, Franz, Martínez-Chantar, María Luz, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Eusko Jaurlaritza, National Institutes of Health (US), National Institute on Alcohol Abuse and Alcoholism (US), Junta de Castilla y León, Junta de Andalucía, European Research Council, German Research Foundation, Ministerio de Educación, Cultura y Deporte (España), Fundació La Marató de TV3, Universidad del País Vasco, Asociación Española Contra el Cáncer, Fundación la Caixa, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Goikoetxea-Usandizaga, Naroa, Bravo, Miren, Egia-Mendikute, Leire, Abecia, Leticia, Serrano-Maciá, Marina, Urdinguio, Rocío G., Clos-García, Marc, Rodríguez-Agudo, Rubén, Araujo-Legido, Raquel, López-Bermudo, Lucía, Delgado, Teresa C., Lachiondo-Ortega, Sofía, González-Recio, Irene, Gil-Pitarch, Clàudia, Peña-Cearra, Ainize, Simón, Jorge, Benedé-Ubieto, Raquel, Ariño, Silvia, Herranz, Jose M., Azkargorta, Mikel, Salazar-Bermeo, Julio, Martí, Nuria, Varela-Rey, Marta, Falcón-Pérez, Juan M., Lorenzo, Óscar, Nogueiras, Rubén, Elortza, Félix, Nevzorova, Yulia, Cubero, Francisco J., Saura, Domingo, Martínez-Cruz, Luis Alfonso, Sabio, Guadalupe, Palazón, Asís, Sancho-Bru, Pau, Elguezabal, Natalia, Fraga, Mario F., Ávila, Matías A., Bataller, Ramón, Marín, José J. G., Martín, Franz, and Martínez-Chantar, María Luz
- Abstract
Background and Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. Approach and Results: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. Conclusions: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.
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- 2023
27. The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.
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Goikoetxea-Usandizaga, Naroa, Bravo, Miren, Egia-Mendikute, Leire, Abecia, Leticia, Serrano-Maciá, Marina, Urdinguio, Rocío G., Clos-García, Marc, Rodríguez-Agudo, Rubén, Araujo-Legido, Raquel, López-Bermudo, Lucía, Delgado, Teresa C., Lachiondo-Ortega, Sofía, González-Recio, Irene, Gil-Pitarch, Clàudia, Peña-Cearra, Ainize, Simón, Jorge, Benedé-Ubieto, Raquel, Ariño, Silvia, Herranz, Jose M., and Azkargorta, Mikel
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- 2023
- Full Text
- View/download PDF
28. Potential role of the mTOR-C1-PGC1α-PPARα axis under type-II diabetes and hypertension in the human heart
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Hang, Tianyu, primary, Lumpuy-Castillo, Jairo, additional, Goikoetxea-Usandizaga, Naroa, additional, Azkargorta, Mikel, additional, Aldámiz, Gonzalo, additional, Martínez-Milla, Juan, additional, Forteza, Alberto, additional, Cortina, JMaría, additional, Egido, Jesús, additional, Elortza, Félix, additional, Martínez-Chantar, Malu, additional, Tuñón, José, additional, and Lorenzo, Óscar, additional
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- 2023
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- View/download PDF
29. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals
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Inmunología, microbiología y parasitología, Immunologia, mikrobiologia eta parasitologia, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Delgado, Teresa C., Simón Espinosa, Jorge, Fernández Ramos, David, Barriales, Diego, Cornide, María E., Jiménez, Mónica, Pérez Redondo, Marina, Lachiondo Ortega, Sofía, Rodríguez Agudo, Rubén, Bizkarguenaga, Maider, Diego Zalamea, Juan, Pasco, Samuel T., Caballero Díaz, Daniel, Alfano, Benedetta, Bravo Garmendia, Miren, González Recio, Irene, Mercado Gómez, María, Gil Pitarch, Clàudia, Mabe Alvarez, Jon, Gracia Sancho, Jordi, Abecia Aliende, Leticia, Lorenzo, Oscar, Martín Sanz, Paloma, Abrescia, Nicola A.G., Sabio, Guadalupe, Rincón, Mercedes, Anguita Castillo, Juan de Dios, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela Rey, Marta, Martínez Chantar, María Luz, Inmunología, microbiología y parasitología, Immunologia, mikrobiologia eta parasitologia, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Delgado, Teresa C., Simón Espinosa, Jorge, Fernández Ramos, David, Barriales, Diego, Cornide, María E., Jiménez, Mónica, Pérez Redondo, Marina, Lachiondo Ortega, Sofía, Rodríguez Agudo, Rubén, Bizkarguenaga, Maider, Diego Zalamea, Juan, Pasco, Samuel T., Caballero Díaz, Daniel, Alfano, Benedetta, Bravo Garmendia, Miren, González Recio, Irene, Mercado Gómez, María, Gil Pitarch, Clàudia, Mabe Alvarez, Jon, Gracia Sancho, Jordi, Abecia Aliende, Leticia, Lorenzo, Oscar, Martín Sanz, Paloma, Abrescia, Nicola A.G., Sabio, Guadalupe, Rincón, Mercedes, Anguita Castillo, Juan de Dios, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela Rey, Marta, and Martínez Chantar, María Luz
- Abstract
[EN] Background and Aims Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models. Approach and Results Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G(1)/S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations. Conclusions Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible o
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- 2022
30. Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis
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Fisiología, Genética, antropología física y fisiología animal, Fisiologia, Genetika,antropologia fisikoa eta animalien fisiologia, Saenz de Urturi Indart, Diego, Buqué García, Xabier, Porteiro, Begoña, Folgueira, Cintia, Mora, Alfonso, Delgado, Teresa C., Prieto Fernández, Endika, Olaizola Rebe, Paula, Gómez Santos, Beatriz, Apodaka Biguri, Maider, González Romero, Francisco, Nieva Zuluaga, Ane, Ruiz de Gauna Madariaga, Mikel, Goikoetxea Usandizaga, Naroa, García Rodríguez, Juan Luis, Gutiérrez de Juan, Virginia, Aurrekoetxea Galindo, Igor, Montalvo Romeral, Valle, Novoa, Eva, Martín Guerrero, Idoia, Varela Rey, Marta, Bhanot, Sanjay, Lee, Richard, Bañales Asurmendi, Jesús María, Syn, Wing-Kin, Sabio, Guadalupe, Martínez Chantar, María Luz, Nogueiras Pozo, Rubén, Aspichueta Celaá, Patricia, Fisiología, Genética, antropología física y fisiología animal, Fisiologia, Genetika,antropologia fisikoa eta animalien fisiologia, Saenz de Urturi Indart, Diego, Buqué García, Xabier, Porteiro, Begoña, Folgueira, Cintia, Mora, Alfonso, Delgado, Teresa C., Prieto Fernández, Endika, Olaizola Rebe, Paula, Gómez Santos, Beatriz, Apodaka Biguri, Maider, González Romero, Francisco, Nieva Zuluaga, Ane, Ruiz de Gauna Madariaga, Mikel, Goikoetxea Usandizaga, Naroa, García Rodríguez, Juan Luis, Gutiérrez de Juan, Virginia, Aurrekoetxea Galindo, Igor, Montalvo Romeral, Valle, Novoa, Eva, Martín Guerrero, Idoia, Varela Rey, Marta, Bhanot, Sanjay, Lee, Richard, Bañales Asurmendi, Jesús María, Syn, Wing-Kin, Sabio, Guadalupe, Martínez Chantar, María Luz, Nogueiras Pozo, Rubén, and Aspichueta Celaá, Patricia
- Abstract
Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis. High methionine and S-adenosylmethionine serum levels are related with obesity. Here the authors show that knockdown of methionine adenosyltransferase by using antisense oligonucleotides provides beneficial effects in obesity and comorbidities.
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- 2022
31. Role of mitochondria in liver diseases
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Martínez Chantar, Mª Luz, Lorenzo González, Oscar, Fisiología, Fisiologia, Goikoetxea Usandizaga, Naroa, Martínez Chantar, Mª Luz, Lorenzo González, Oscar, Fisiología, Fisiologia, and Goikoetxea Usandizaga, Naroa
- Abstract
252 p., La disfunción mitocondrial desempeña un papel clave en el inicio y desarrollo de las enfermedades hepáticas crónicas. La proteína J controlada por metilación (MCJ) es un inhibidor endógeno de laactividad mitocondrial, y previamente hemos podido demostrar niveles significativamente aumentados deMCJ en pacientes con hígado graso, daño hepático inducido por paracetamol y lesión hepática debido a la colestasis, lo que sugiere una posible asociación entre MCJ y la disfunción mitocondrial. La enfermedad hepática alcohólica causa más de 2 millones de fallecimientos en el mundo y es la segunda causa detrasplante hepático. Sin embargo, carece de un tratamiento específico. Por otro lado, las tasas actuales de trasplante hepático cubren menos del 10% de las necesidades globales, y entre las estrategias paraaumentar el grupo de donantes, se ha propuesto el uso de hígado con criterio expandido, aquellos queprovienen de hígados añosos o esteatóticos. Sin embargo, el uso de estos órganos aumenta el fallo hepático post trasplante, ya que su capacidad regenerativa está limitada y sufren una alta susceptibilidad hacia el daño por isquemia. En ambos modelos la disfunción mitocondrial es un indicador temprano deldaño hepático y hemos podido comprobar la sobreexpresión de MCJ en estadios avanzados. De hecho, elsilenciamiento hepático de MCJ (1) recupera la actividad mitocondrial, alivia la esteatosis y evita la inflamación y el estrés oxidativo en modelos preclínicos de enfermedad hepática alcohólica, y (2) acelerala regeneración hepática y reduce la lesión isquémica en ratones jóvenes, pero significativamente,también en ratones añosos y esteatóticos, promoviendo su uso para el trasplante hepático, reduciendo así la escasez existente de donantes. En resumen, este proyecto muestra la contribución de la disfunción mitocondrial, en especial de la proteína MCJ, en el desarrollo de la enfermedad hepática alcohólica y la regeneración limitada junto con mayor susceptibilidad isquémica que se o
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- 2022
32. Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage
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Bioquímica y biología molecular, Inmunología, microbiología y parasitología, Biokimika eta biologia molekularra, Immunologia, mikrobiologia eta parasitologia, González Recio, Irene, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Mercado Gómez, María, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Gil Pitarch, Clàudia, Fernández Rodríguez, Carmen, Castellana, Donatello, Latasa, María Ujué, Abecia Aliende, Leticia, Anguita Castillo, Juan de Dios, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín Plágaro, César Augusto, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raúl, Lucena, M. Isabel, Buccella, Daniela, Martínez de la Cruz, Alfonso, Martínez Chantar, María Luz, Bioquímica y biología molecular, Inmunología, microbiología y parasitología, Biokimika eta biologia molekularra, Immunologia, mikrobiologia eta parasitologia, González Recio, Irene, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Mercado Gómez, María, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Gil Pitarch, Clàudia, Fernández Rodríguez, Carmen, Castellana, Donatello, Latasa, María Ujué, Abecia Aliende, Leticia, Anguita Castillo, Juan de Dios, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín Plágaro, César Augusto, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raúl, Lucena, M. Isabel, Buccella, Daniela, Martínez de la Cruz, Alfonso, and Martínez Chantar, María Luz
- Abstract
Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models. Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.
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- 2022
33. Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comisión Asesora de Investigación Científica y Técnica, CAICYT (España), Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, European Joint Programme on Rare Diseases, Instituto de Salud Carlos III, National Institutes of Health (US), Newcastle Biobanks, Cancer Research UK, González-Recio, Irene, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Fernández-Rodríguez, Carmen, Castellana, Donatello, Latasa, Maria U., Abecia, Leticia, Anguita, Juan, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín, César, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti, Reeves, Helen L., Andrade, Raúl J., Lucena, María Isabel, Buccella, Daniela, Martínez-Cruz, Luis Alfonso, Martínez-Chantar, María Luz, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comisión Asesora de Investigación Científica y Técnica, CAICYT (España), Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, European Joint Programme on Rare Diseases, Instituto de Salud Carlos III, National Institutes of Health (US), Newcastle Biobanks, Cancer Research UK, González-Recio, Irene, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Fernández-Rodríguez, Carmen, Castellana, Donatello, Latasa, Maria U., Abecia, Leticia, Anguita, Juan, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín, César, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti, Reeves, Helen L., Andrade, Raúl J., Lucena, María Isabel, Buccella, Daniela, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, María Luz
- Abstract
Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.
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- 2022
34. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals
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Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Delgado, Teresa C., Simón, Jorge, Fernández-Ramos, David, Barriales, Diego, Cornide, Maria E., Jiménez, Mónica, Pérez-Redondo, Marina, Lachiondo-Ortega, Sofía, Rodríguez-Agudo, Rubén, Bizkarguenaga, Maider, Zalamea, Juan Diego, Pasco, Samuel T., Caballero-Díaz, Daniel, Alfano, Benedetta, Bravo, Miren, González-Recio, Irene, Mercado-Gomez, María, Gil-Pitarch, Clàudia, Mabe, Jon, Gracia-Sancho, Jordi, Abecia, Leticia, Lorenzo, Óscar, Martín-Sanz, Paloma, Abrescia, Nicola G. A., Sabio, Guadalupe, Rincón, Mercedes, Anguita, Juan, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela-Rey, Marta, Martínez-Chantar, María Luz, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Delgado, Teresa C., Simón, Jorge, Fernández-Ramos, David, Barriales, Diego, Cornide, Maria E., Jiménez, Mónica, Pérez-Redondo, Marina, Lachiondo-Ortega, Sofía, Rodríguez-Agudo, Rubén, Bizkarguenaga, Maider, Zalamea, Juan Diego, Pasco, Samuel T., Caballero-Díaz, Daniel, Alfano, Benedetta, Bravo, Miren, González-Recio, Irene, Mercado-Gomez, María, Gil-Pitarch, Clàudia, Mabe, Jon, Gracia-Sancho, Jordi, Abecia, Leticia, Lorenzo, Óscar, Martín-Sanz, Paloma, Abrescia, Nicola G. A., Sabio, Guadalupe, Rincón, Mercedes, Anguita, Juan, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela-Rey, Marta, and Martínez-Chantar, María Luz
- Abstract
[Background and aims ]Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models., [Approach and results] Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations., [Conclusions] Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.
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- 2022
35. Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen
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Rodríguez-Agudo, Rubén, primary, Goikoetxea-Usandizaga, Naroa, additional, Serrano-Maciá, Marina, additional, Fernández-Tussy, Pablo, additional, Fernández-Ramos, David, additional, Lachiondo-Ortega, Sofía, additional, González-Recio, Irene, additional, Gil-Pitarch, Clàudia, additional, Mercado-Gómez, María, additional, Morán, Laura, additional, Bizkarguenaga, Maider, additional, Lopitz-Otsoa, Fernando, additional, Petrov, Petar, additional, Bravo, Miren, additional, Van Liempd, Sebastiaan Martijn, additional, Falcon-Perez, Juan Manuel, additional, Zabala-Letona, Amaia, additional, Carracedo, Arkaitz, additional, Castell, Jose Vicente, additional, Jover, Ramiro, additional, Martínez-Cruz, Luis Alfonso, additional, Delgado, Teresa Cardoso, additional, Cubero, Francisco Javier, additional, Lucena, María Isabel, additional, Andrade, Raúl Jesús, additional, Mabe, Jon, additional, Simón, Jorge, additional, and Martínez-Chantar, María Luz, additional
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- 2022
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36. Role of mitochondria in liver diseases
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Goikoetxea Usandizaga, Naroa, Martínez Chantar, Mª Luz, and Lorenzo González, Oscar
- Subjects
trasplante de órganos ,gastroenterología ,organ transplantation ,gastroenterology - Abstract
252 p. La disfunción mitocondrial desempeña un papel clave en el inicio y desarrollo de las enfermedades hepáticas crónicas. La proteína J controlada por metilación (MCJ) es un inhibidor endógeno de laactividad mitocondrial, y previamente hemos podido demostrar niveles significativamente aumentados deMCJ en pacientes con hígado graso, daño hepático inducido por paracetamol y lesión hepática debido a la colestasis, lo que sugiere una posible asociación entre MCJ y la disfunción mitocondrial. La enfermedad hepática alcohólica causa más de 2 millones de fallecimientos en el mundo y es la segunda causa detrasplante hepático. Sin embargo, carece de un tratamiento específico. Por otro lado, las tasas actuales de trasplante hepático cubren menos del 10% de las necesidades globales, y entre las estrategias paraaumentar el grupo de donantes, se ha propuesto el uso de hígado con criterio expandido, aquellos queprovienen de hígados añosos o esteatóticos. Sin embargo, el uso de estos órganos aumenta el fallo hepático post trasplante, ya que su capacidad regenerativa está limitada y sufren una alta susceptibilidad hacia el daño por isquemia. En ambos modelos la disfunción mitocondrial es un indicador temprano deldaño hepático y hemos podido comprobar la sobreexpresión de MCJ en estadios avanzados. De hecho, elsilenciamiento hepático de MCJ (1) recupera la actividad mitocondrial, alivia la esteatosis y evita la inflamación y el estrés oxidativo en modelos preclínicos de enfermedad hepática alcohólica, y (2) acelerala regeneración hepática y reduce la lesión isquémica en ratones jóvenes, pero significativamente,también en ratones añosos y esteatóticos, promoviendo su uso para el trasplante hepático, reduciendo así la escasez existente de donantes. En resumen, este proyecto muestra la contribución de la disfunción mitocondrial, en especial de la proteína MCJ, en el desarrollo de la enfermedad hepática alcohólica y la regeneración limitada junto con mayor susceptibilidad isquémica que se observa en hígados con un metabolismo comprometido, con el objetivo de establecer dicha proteína como futura diana terapéutica para el tratamiento de enfermedades hepáticas crónicas
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- 2022
37. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals
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Goikoetxea‐Usandizaga, Naroa, primary, Serrano‐Maciá, Marina, additional, Delgado, Teresa C., additional, Simón, Jorge, additional, Fernández Ramos, David, additional, Barriales, Diego, additional, Cornide, Maria E., additional, Jiménez, Mónica, additional, Pérez‐Redondo, Marina, additional, Lachiondo‐Ortega, Sofia, additional, Rodríguez‐Agudo, Rubén, additional, Bizkarguenaga, Maider, additional, Zalamea, Juan Diego, additional, Pasco, Samuel T., additional, Caballero‐Díaz, Daniel, additional, Alfano, Benedetta, additional, Bravo, Miren, additional, González‐Recio, Irene, additional, Mercado‐Gómez, Maria, additional, Gil‐Pitarch, Clàudia, additional, Mabe, Jon, additional, Gracia‐Sancho, Jordi, additional, Abecia, Leticia, additional, Lorenzo, Óscar, additional, Martín‐Sanz, Paloma, additional, Abrescia, Nicola G. A., additional, Sabio, Guadalupe, additional, Rincón, Mercedes, additional, Anguita, Juan, additional, Miñambres, Eduardo, additional, Martín, César, additional, Berenguer, Marina, additional, Fabregat, Isabel, additional, Casado, Marta, additional, Peralta, Carmen, additional, Varela‐Rey, Marta, additional, and Martínez‐Chantar, María Luz, additional
- Published
- 2021
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38. Mitochondrial physiology: Gnaiger Erich et al ― MitoEAGLE Task Group
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Gnaiger, Erich, Aasander Frostner, Eleonor, Abdul Karim, Norwahidah, Abdel-Rahman, Engy Ali, Abumrad, Nada A, Acuna-Castroviejo, Dario, Adiele, Reginald C, Ahn, Bumsoo, Alencar, MB, Ali, Sameh S, Almeida, Angeles, Alton, Lesley, Alves, Marco G, Amati, Francesca, Amoedo, Nivea Dias, Amorim, Ricardo, Anderson, Ethan J, Andreadou, Ioanna, Antunes, Diana, Arago, Marc, Aral, Cenk, Arandarcikaite, Odeta, Arias-Reyes, Christian, Armand, Anne-Sophie, Arnould, Thierry, Avram, Vlad Florian, Axelrod, Christopher L, Bairam, Aida, Bailey, Damian M, Bajpeyi, Sudip, Bajzikova, Martina, Bakker, Barbara M, Barlow, Jonathan, Bardal, Tora, Banni, A, Bastos Sant'Anna Silva, Ana Carolina, Batterson, Philip, Battino, Maurizio, Bazil, Jason, Beard, Daniel A, Beleza, Jorge, Bednarczyk, Piotr, Bello, Fiona, Ben-Shachar, Dorit, Bento Guida, Jose Freitas, Bergdahl, Andreas, Berge, Rolf K, Bergmeister, Lisa, Bernardi, Paolo, Berridge, Michael V, Bettinazzi, Stefano, Bishop, David, Blier, Pierre U, Blindheim, Dan Filip, Boardman, Neoma T, Boetker, Hans Erik, Borchard, Sabine, Boros, Mihaly, Borsheim, Elisabet, Borras, Consuelo, Borutaite, Vilma, Botella, Javier, Bouillaud, Frederic, Bouitbir, Jamal, Boushel, Robert C, Bovard, Josh, Bravo-Sagua, Roberto, Breton, Sophie, Brown, David A, Brown, Guy C, Brown, Robert A, Brozinick, Joseph T, Buettner, Garry R, Burtscher, Johannes, Bustos, Matilde, Calabria, Elisa, Calbet, Jose A, Calzia, Enrico, Cannon, Daniel T, Cano Sanchez, Maria, Canto Alvarez, Carles, Cardinale, D, Cardoso, Luiza Helena Daltro, Carvalho, Eugenia, Casado Pinna, Marta, Cassar, Samantha, Castelo, Maria P, Castilho, Roger F, Cavalcanti-de-Albuquerque, Joao Paulo, Cecatto, Cristiane, Celen, Murat C, Cervinkova, Zuzana, Chabi, Beatrice, Chakrabarti, Lisa, Chakrabarti, Sasanka, Chaurasia, Bhagirath, Chen, Quan, Chicco, Adam J, Chinopoulos, Christos, Chowdhury, Subir K, Cizmarova, Beata, Clementi, Emilio, Coen, Paul M, Cohen, Bruce H, Coker, Robert H, Collin-Chenot, Anne, Coughlan, Melinda T, Coxito, Petro, Crisostomo, Luis, Crispim, Marcell, Crossland, Hannah, Dahdah, Norma, Dalgaard, Louise T, Dambrova, Maija, Danhelovska, Tereza, Darveau, Charles A, Darwin, Paula M, Das, Anibh M, Dash, Ranjan K, Davidova, Eliska, Davis, Michael S, Dayanidhi, Sudarshan, De Bem, Andreza Fabro, De Goede, Paul, De Palma, Clara, De Pinto, Vito, Dela, F, Dembinska-Kiec, Aldona, Detraux, Damien, Devaux, Yvan, Di Marcello, Marco, Di Paola, Floriana Jessica, Dias, Candida, Dias, Tania R, Diederich, Marc, Distefano, Giovanna, Djafarzadeh, Siamak, Doermann, Niklas, Doerrier, Carolina, Dong, Lan-Feng, Donnelly, Chris, Drahota, Zdenek, Duarte, Filipe Valente, Dubouchaud, Herve, Duchen, Michael R, Dumas, Jean-Francois, Durham, William J, Dymkowska, Dorota, Dyrstad, Sissel E, Dyson, Alex, Dzialowski, Edward M, Eaton, Simon, Ehinger, Johannes, Elmer, Eskil, Endlicher, Rene, Engin, Ayse B, Escames, Germaine, Evinova, Andrea, Ezrova, Zuzana, Falk, Marni Joy, Fell, David A, Ferdinandy, Peter, Ferko, Miroslav, Fernandez-Ortiz, Marisol, Erika, Fernandez-Vizarra, Ferreira, Julio Cesar Batista, Ferreira, Rita, Ferri, Alessandra, Festuccia, WT, Fessel, Joshua P, Filipovska, Aleksandra, Fisar, Zdenek, Fischer, Christine, Fischer, Michael, Fisher, Gordon, Fisher, Joshua J, Fontanesi, Flavia, Forbes-Hernandez, Tamara Y, Ford, Ellen, Fornaro, Mara, Fuertes Agudo, Marina, Fulton, Montana, Galina, Antonio, Galkin, Alexander, Gallee, Leon, Galli, Gina L, Gama Perez, Pau, Gan, Zhenji, Ganetzky, Rebecca, Gao, Yun, Garcia, Geovana S, Garcia-Rivas, Gerardo, Garcia-Roves, Pablo Miguel, Garcia-Souza, Luiz Felipe, Garlid, Keith D, Garrabou, Gloria, Garten, Antje, Gastaldelli, Amalia, Gayen, Jiaur, Genders, Amanda J, Genova, Maria Luisa, Giampieri, Francesca, Glatz, Jan FC, Giovarelli, Matteo, Goikoetxea Usandizaga, Naroa, Goncalo Teixeira da Silva, Rui, Goncalves, Debora Farina, Gonzalez-Armenta, Jenny L, Gonzalez-Francesqua, A, Gonzalez-Freire, Marta, Gonzalo, Hugo, Goodpaster, Bret H, Gorr, Thomas A, Gourlay, Campbell W, Grams, Bente, Granata, Cesare, Grefte, Sander, Grilo, Luis, Guarch, Meritxell Espino, Gueguen, Naig, Gumeni, Sentiljana, Haas, Clarissa B, Haavik, Jan, Hachmo, Yafit, Haendeler, Judith, Haider, Markus, Hajrulahovic, Anesa, Hamann, Andrea, Han, Jin, Han, Woo Hyun, Hancock, Chad R, Hand, Steven C, Handl, Jiri, Hansikova, Hana, Hardee, Justin P, Hargreaves, Ian P, Harper, Mary Ellen, Harrison, David K, Hassan, Hazirah, Hatakova, Zuzana, Hausenloy, Derek J, Heales, Simon JR, Heiestad, Christina, Hellgren, Kim T, Henrique, Alexandrino, Hepple, Russell T, Hernansanz-Agustin, Pablo, Hewakapuge, Sudinna, Hickey, Anthony J, Ho, Dieu Hien, Hoehn, Kyle L, Hoel, Frederik, Holland, Olivia J, Holloway, Graham P, Holzner, Lorenz, Hoppel, Charles L, Hoppeler, H, Hoppel, Florian, Houstek, Josef, Huete-Ortega, Maria, Hyrossova, Petra, Iglesias-Gonzalez, Javier, Indiveri, Cesare, Irving, Brian A, Isola, Raffaella, Iyer, Shilpa, Jackson, Christophe B, Jadiya, Pooja, Jana, Prado Fabian, Jandeleit-Dahm, K, Jang, David H, Jang, Young C, Janowska, Joanna, Jansen, Kirsten, Jansen-Duerr, Pidder, Jansone, Baiba, Jarmuszkiewicz, Wieslawa, Jaskiewicz, Anna, Jaspers, Richard T, Jedlicka, Jan, Jerome, Estaquier, Jespersen, Nichlas R, Jha, Rajan K, Joseph, Vincent, Juhasz, Laszlo, Jurczak, Michael J, Jurk, Diana, Kaambre, Tuuli, Kaczor, Jan J, Kainulainen, Heikki, Kampa, Rafal Pawel, Kandel, Sunil M, Kane, Daniel A, Kapferer, Werner, Kapnick, Senta, Kappler, Lisa, Karabatsiakis, Alexander, Karavaeva, Iuliia, Karkucinska-Wieckowska, Agnieszka, Kaur, Sarbjot, Keijer, Jaap, Keller, Markus A, Keppner, Gloria, Khamoui, Andy V, Kidere, Dita, Kilbaugh, Todd, Kim, Hyoung Kyu, Kim, Julian KS, Kimoloi, Sammy, Klepinin, Aleksandr, Klepinina, Lyudmila, Klingenspor, Martin, Klocker, Helmut, Komlódi, Timea, Kolasa, Iris, Koopman, Werner JH, Kopitar-Jerala, Natasa, Kowaltowski, Alicia J, Kozlov, Andrey V, Krajcova, Adela, Krako Jakovljevic, Nina, Kristal, Bruce S, Krycer, Jamer R, Kuang, Jujiao, Kucera, Otto, Kuka, Janis, Kwak, Hyo Bum, Kwast, Kurt, Kwon, Oh Sung, Laasmaa, Martin, Labieniec-Watala, Magdalena, Lai, Nicola, Lalic, Nebojsa M, Land, John M, Lane, Nick, Laner, Verena, Lanza, Ian R, Laouafa, Sofien, Larsen, Steen, Larsen, Terje S, Lavery, Gareth G, Lazou, Antigone, Ledo, Ana Margarida, Lee, Hong Kyu, Leeuwenburgh, Christiaan, Lehti, Maarit, Lemieux, Helene, Lenaz, Giorgio, Lerfall, Jorgen, Li, Pingan A, Li Puma, Lance, Liang, Liping, Liepins, Edgars, Lin, Chien-Te, Liu, Jiankang, Lopez, Luis C, Lucchinetti, Eliana, Ma, Tao, Macedo, Maria P, Machado, Ivo F, Maciej, Sarah, MacMillan-Crow, Lee Ann, Magalhaes, Jose, Magri, Andrea, Majtnerova, Pavlina, Makarova, Elina, Makrecka-Kuka, Marina, Malik, Afshan N, Marcouiller, Francois, Marechal, Amandine, Markova, Michaela, Markovic, Ivanka, Martin, Daniel S, Martins, Ana Dias, Martins, Joao D, Maseko, Tumisang Edward, Maull, Felicia, Mazat, Jean Pierre, McKenna, Helen T, McKenzie, Matthew, McMillan, Duncan GG, McStay, Gavin P, Menze, Michael A, Mendham, Amy, Mercer, John R, Merz, Tamara, Messina, Angela, Meszaros, Andras T, Methner, Axel, Michalak, Slawomir, Mila Guasch, Maria, Minuzzi, Luciele M, Misirkic Marjanovic, Maja, Moellering, Douglas R, Moisoi, Nicoleta, Molina, Anthony JA, Montaigne, David, Moore, Anthony L, Moore, Christy, Moreau, Kerrie, Moreira, Bruno P, Moreno-Sanchez, Rafael, Mracek, Tomas, Muccini, Anna Maria, Muntane, Jordi, Muntean, Danina M, Murray, Andrew J, Musiol, Eva, Nabben, Miranda, Nair, K Sreekumaran, Nehlin, Jan O, Nemec, Michal, Nesci, Salvatore, Neufer, P Darrell, Neuzil, Jiri, Neviere, Remi, Newsom, Sean A., Norman, Jennifer, Nozickova, Katerina, Nunes, Sara, Nuoffer, Jean-Marc, O'Brien, Kristin, O'Brien, Katie A, O'Gorman, Donal, Olgar, Yusuf, Oliveira, Ben, Oliveira, Jorge, Oliveira, Marcus F, Oliveira, Marcos Tulio, Oliveira, Pedro F, Oliveira, Paulo J, Olsen, Rolf Erik, Orynbayeva, Zulfiya, Osiewacz, Heinz D, Paez, Hector, Pak, Youngmi K, Pallotta, Maria L, Palmeira, Carlos M, Parajuli, Nirmala, Passos, Joao F, Passrugger, Manuela, Patel, Hemal H, Pavlova, Nadia, Pavlovic, Kasja, Pecina, Petr, Pedersen, Tina M, Perales, Jose Carlos, Pereira da Silva Grilo da Silva, Filomena, Pereira, Rita, Perez Valencia, Juan A, Perks, Kara L, Pesta, Dominik, Petit, Patrice X, Pettersen Nitschke, Ina Katrine, Pichaud, Nicolas, Pichler, Irene, Piel, Sarah, Pietka, Terri A, Pinho, Sonia A, Pino, Maria F, Pirkmajer, Sergej, Place, Nicolas, Plangger, Mario, Porter, Craig, Porter, Richard K, Preguica, Ines, Procaccio, Vincent, Prochownik, Edward V, Prola, Alexandre, Pulinilkunnil, Thomas, Puskarich, Michael A, Puurand, Marju, Radenkovic, Filip, Ramzan, Rabia, Rattan, Suresh IS, Reano, Simone, Reboredo, Patricia, Rees, Bernard B, Renner-Sattler, Kathrin, Rial, Eduardo, Robinson, Matthew M, Roden, Michael, Rodrigues, Ana Sofia, Rodriguez, Enrique, Rodriguez-Enriquez, Sara, Roesland, Gro Vatne, Rolo, Anabela Pinto, Ropelle, Eduardo R, Roshanravan, Baback, Rossignol, Rodrigue, Rossiter, Harry B, Rousar, Tomas, Rubelj, Ivica, Rybacka-Mossakowska, Joanna, Saada, Ann, Safaei, Zahra, Sarlak, Saharnaz, Salin, Karine, Salvadego, Desy, Sandi, Carmen, Saner, Nicholas, Santos, Diana, Sanz, Alberto, Sardao, Vilma, Sazanov, Leonid A, Scaife, Paula, Scatena, Roberto, Schartner, Melanie, Scheibye-Knudsen, Morten, Schilling, Jan M, Schlattner, Uwe, Schmitt, Sabine, Schneider Gasser, Edith Mariane, Schoenfeld, Peter, Schots, Pauke C, Schulz, Rainer, Schwarzer, Christoph, Scott, Graham R, Selman, Colin, Sendon, Pamella Marie, Shabalina, Irina G, Sharma, Pushpa, Sharma, Vipin, Shevchuk, Igor, Shirazi, Reza, Shiroma, Jonathan G, Siewiera, Karolina, Silber, Ariel M, Silva, Ana Maria, Sims, Carrie A, Singer, Dominique, Singh, Brijesh Kumar, Skolik, Robert A, Smenes, Benedikte Therese, Smith, James, Soares, Félix Alexandre Antunes, Sobotka, Ondrej, Sokolova, Inna, Solesio Torregrosa, M De la Encarnacion, Soliz, Jorge, Sonkar, Vijay K, Sova, Marina, Sowton, Alice P, Sparagna, Genevieve C, Sparks, Lauren M, Spinazzi, Marco, Stankova, Pavla, Starr, Jonathan, Stary, Creed, Stefan, Eduard, Stelfa, Gundega, Stepto, Nigel K, Stevanovic, Jelena, Stiban, Johnny, Stier, Antoine, Stocker, Roland, Storder, Julie, Sumbalova, Zuzana, Suomalainen, Wartiovaara Anu, Suravajhala, Prashanth, Svalbe, Baiba, Swerdlow, Russel H, Swiniuch, Daria, Szabo, Ildiko, Szewczyk, Adam, Szibor, Marten, Tanaka, Masashi, Tandler, Bernard, Tarnopolsky, Mark A, Tausan, Daniel, Tavernarakis, Nektarios, Tepp, Kersti, Teodoro, J, Thakkar, Himani, Thapa, Maheshwo, Thyfault, John P, Tomar, Dhanendra, Ton, Riccardo, Torp, May-Kristin, Torres-Quesada, Omar, Towheed, Atif, Treberg, Jason R, Tretter, Laszlo, Trewin, Adam J, Trifunovic, Aleksandra, Trivigno, Catherine, Tronstad, Karl Johan, Trougakos, Ioannis P, Truu, Laura, Tuncay, Erkan, Turan, Belma, Tyrrell, Daniel J, Urban, Tomas, Urner, Sofia, Valentine, Joseph Marco, Van Bergen, Nicole J, Van der Ende, Miranda, Varricchio, Frederick, Vaupel, Peter, Vella, Joanna, Vendelin, Marko, Verdaguer, IB, Vercesi, Anibal E, Vernerova, Andrea, Victor, Victor Manuel, Vieira Ligo Teixeira, Camila, Vidimce, Josif, Viel, Christian, Vieyra, Adalberto, Vilks, Karlis, Villena, Joseph A, Vincent, Vinnyfred, Vinogradov, Andrey D, Viscomi, Carlo, Vitorino, Rui Miguel Pinheiro, Vlachaki Walker, Julia, Vogt, Sebastian, Volani, Chiara, Volska, Kristine, Votion, Dominique-Marie, Vujacic-Mirski, Ksenija, Wagner, Brett A, Ward, Marie Louise, Warnsmann, Verena, Wasserman, David H, Watala, Cezary, Wei, Yau-Huei, Weinberger, Klaus M, White, Sarah, Whitfield, Jamie, Wickert, Anika, Wieckowski, Mariusz R, Wiesner, Rudolf J, Williams, Caroline M, Winwood-Smith, Hugh, Wohlgemuth, Stephanie E, Wohlwend, Martin, Wolff, Jonci Nikolai, Wrutniak-Cabello, Chantal, Wuest, Rob C I, Yokota, Takashi, Zablocki, Krzysztof, Zanon, Alessandra, Zanou, Nadege, Zaugg, Kathrin, Zaugg, Michael, Zdrazilova, Lucie, Zhang, Yong, Zhang, Yi Zhu, Zikova, Alena, Zischka, Hans, Zorzano, Antonio, Zujovic, Tijana, Zurmanova, Jitka, Zvejniece, Liga, Lagarrigue, Sylviane, Munro, Daniel, Pereira, Susana, Laranjinha, Joäo, Hecker, Matthias, Jusic, Amela, Prigione, Alessandro, Sommer, Natascha, Weissig, Volkmar, Guida, Bento, G, John G, Jones, JG, AMS - Tissue Function & Regeneration, AMS - Rehabilitation & Development, Physiology, Mito-Eagle - Evolution-Age-Gender-Lifestyle-Environment (Mito-Eagle), Oroboros Instruments, Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Gnaiger Erich, Aasander Frostner Eleonor, Abdul Karim Norwahidah, Abdel-Rahman Engy Ali, Abumrad Nada A, Acuna-Castroviejo Dario, Adiele Reginald C, Ahn Bumsoo, Alencar Mayke Bezerra, Ali Sameh S, Almeida Angeles, Alton Lesley, Alves Marco G, Amati Francesca, Amoedo Nivea Dias, Amorim Ricardo, Anderson Ethan J, Andreadou Ioanna, Antunes Diana, Arago Marc, Aral Cenk, Arandarcikaite Odeta, Arias-Reyes Christian, Armand Anne-Sophie, Arnould Thierry, Avram Vlad F, Axelrod Christopher L, Bailey Damian M, Bairam Aida, Bajpeyi Sudip, Bajzikova Martina, Bakker Barbara M, Banni Aml, Bardal Tora, Barlow J, Bastos Sant'Anna Silva Ana Carolina, Batterson Philip M, Battino Maurizio, Bazil Jason N, Beard Daniel A, Bednarczyk Piotr, Beleza Jorge, Bello Fiona, Ben-Shachar Dorit, Bento Guida Jose Freitas, Bergdahl Andreas, Berge Rolf K, Bergmeister Lisa, Bernardi Paolo, Berridge Michael V, Bettinazzi Stefano, Bishop David J, Blier Pierre U, Blindheim Dan Filip, Boardman Neoma T, Boetker Hans Erik, Borchard Sabine, Boros Mihaly, Boersheim Elisabet, Borras Consuelo, Borutaite Vilma, Botella Javier, Bouillaud Frederic, Bouitbir Jamal, Boushel Robert C, Bovard Josh, Bravo-Sagua Roberto, Breton Sophie, Brown David A, Brown Guy C, Brown Robert Andrew, Brozinick Joseph T, Buettner Garry R, Burtscher Johannes, Bustos Matilde, Calabria Elisa, Calbet Jose AL, Calzia Enrico, Cannon Daniel T, Cano Sanchez Maria Consolacion, Canto Alvarez Carles, Cardinale Daniele A, Cardoso Luiza HD, Carvalho Eugenia, Casado Pinna Marta, Cassar Samantha, Castelo Rueda Maria Paulina, Castilho Roger F, Cavalcanti-de-Albuquerque Joao Paulo, Cecatto Cristiane, Celen Murat C, Cervinkova Zuzana, Chabi Beatrice, Chakrabarti Lisa, Chakrabarti Sasanka, Chaurasia Bhagirath, Chen Quan, Chicco Adam J, Chinopoulos Christos, Chowdhury Subir Kumar, Cizmarova Beata, Clementi Emilio, Coen Paul M, Cohen Bruce H, Coker Robert H, Collin-Chenot Anne, Coughlan Melinda T, Coxito Pedro, Crisostomo Luis, Crispim Marcell, Crossland Hannah, Dahdah Norma Ramon, Dalgaard Louise T, Dambrova Maija, Danhelovska Tereza, Darveau Charles-A, Darwin Paula M, Das Anibh Martin, Dash Ranjan K, Davidova Eliska, Davis Michael S, Dayanidhi Sudarshan, De Bem Andreza Fabro, De Goede Paul, De Palma Clara, De Pinto Vito, Dela Flemming, Dembinska-Kiec Aldona, Detraux Damian, Devaux Yvan, Di Marcello Marco, Di Paola Floriana Jessica, Dias Candida, Dias Tania R, Diederich Marc, Distefano Giovanna, Djafarzadeh Siamak, Doermann Niklas, Doerrier Carolina, Dong Lan-Feng, Donnelly Chris, Drahota Zdenek, Duarte Filipe Valente, Dubouchaud Herve, Duchen Michael R, Dumas Jean-Francois, Durham William J, Dymkowska Dorota, Dyrstad Sissel E, Dyson Alex, Dzialowski Edward M, Eaton Simon, Ehinger Johannes K, Elmer Eskil, Endlicher Rene, Engin Ayse Basak, Escames Germaine, Evinova Andrea, Ezrova Zuzana, Falk Marni J, Fell David A, Ferdinandy Peter, Ferko Miroslav, Fernandez-Ortiz Marisol, Fernandez-Vizarra Erika, Ferreira Julio Cesar B, Ferreira Rita Maria P, Ferri Alessandra, Fessel Joshua Patrick, Festuccia William T, Filipovska Aleksandra, Fisar Zdenek, Fischer Christine, Fischer Michael J, Fisher Gordon, Fisher Joshua J, Fontanesi Flavia, Forbes-Hernandez Tamara Y, Ford Ellen, Fornaro Mara, Fuertes Agudo Marina, Fulton Montana, Galina Antonio, Galkin Alexander, Gallee Leon, Galli Gina L J, Gama Perez Pau, Gan Zhenji, Ganetzky Rebecca, Gao Yun, Garcia Geovana S, Garcia-Rivas Gerardo, Garcia-Roves Pablo Miguel, Garcia-Souza Luiz F, Garlid Keith D, Garrabou Gloria, Garten Antje, Gastaldelli Amalia, Gayen Jiaur, Genders Amanda J, Genova Maria Luisa, Giampieri Francesca, Giovarelli Matteo, Glatz Jan FC, Goikoetxea Usandizaga Naroa, Goncalo Teixeira da Silva Rui, Goncalves Debora Farina, Gonzalez- Armenta Jenny L, Gonzalez-Franquesa Alba, Gonzalez-Freire Marta, Gonzalo Hugo, Goodpaster Bret H, Gorr Thomas A, Gourlay Campbell W, Grams Bente, Granata Cesare, Grefte Sander, Grilo Luis, Guarch Meritxell Espino, Gueguen Naig, Gumeni Sentiljana, Haas Clarissa, Haavik Jan, Hachmo Yafit, Haendeler Judith, Haider Markus, Hajrulahovic Anesa, Hamann Andrea, Han Jin, Han Woo Hyun, Hancock Chad R, Hand Steven C, Handl Jiri, Hansikova Hana, Hardee Justin P, Hargreaves Iain P, Harper Mary- Ellen, Harrison David K, Hassan Hazirah, Hatokova Zuzana, Hausenloy Derek J, Heales Simon JR, Hecker Matthias, Heiestad Christina, Hellgren Kim T, Henrique Alexandrino, Hepple Russell T, Hernansanz- Agustin Pablo, Hewakapuge Sudinna, Hickey Anthony J, Ho Dieu Hien, Hoehn Kyle L, Hoel Fredrik, Holland Olivia J, Holloway Graham P, Holzner Lorenz, Hoppel Charles L, Hoppel Florian, Hoppeler Hans, Houstek Josef, Huete-Ortega Maria, Hyrossova Petra, Iglesias-Gonzalez Javier, Indiveri Cesare, Irving Brian A, Isola Raffaella, Iyer Shilpa, Jackson Christopher Benjamin, Jadiya Pooja, Jana Prado Fabian, Jandeleit-Dahm Karin, Jang David H, Jang Young Charles, Janowska Joanna, Jansen Kirsten M, Jansen-Duerr Pidder, Jansone Baiba, Jarmuszkiewicz Wieslawa, Jaskiewicz Anna, Jaspers Richard T, Jedlicka Jan, Jerome Estaquier, Jespersen Nichlas Riise, Jha Rajan Kumar, Jones John G, Joseph Vincent, Juhasz Laszlo, Jurczak Michael J, Jurk Diana, Jusic Amela, Kaambre Tuuli, Kaczor Jan Jacek, Kainulainen Heikki, Kampa Rafal Pawel, Kandel Sunil Mani, Kane Daniel A, Kapferer Werner, Kapnick Senta, Kappler Lisa, Karabatsiakis Alexander, Karavaeva Iuliia, Karkucinska-Wieckowska Agnieszka, Kaur Sarbjot, Keijer Jaap, Keller Markus A, Keppner Gloria, Khamoui Andy V, Kidere Dita, Kilbaugh Todd, Kim Hyoung Kyu, Kim Julian KS, Kimoloi Sammy, Klepinin Aleksandr, Klepinina Lyudmila, Klingenspor Martin, Klocker Helmut, Kolassa Iris, Komlodi Timea, Koopman Werner JH, Kopitar-Jerala Natasa, Kowaltowski Alicia J, Kozlov Andrey V, Krajcova Adela, Krako Jakovljevic Nina, Kristal Bruce S, Krycer James R, Kuang Jujiao, Kucera Otto, Kuka Janis, Kwak Hyo Bum, Kwast Kurt E, Kwon Oh Sung, Laasmaa Martin, Labieniec-Watala Magdalena, Lagarrigue Sylviane, Lai Nicola, Lalic Nebojsa M, Land John M, Lane Nick, Laner Verena, Lanza Ian R, Laouafa Sofien, Laranjinha Joao, Larsen Steen, Larsen Terje S, Lavery Gareth G, Lazou Antigone, Ledo Ana Margarida, Lee Hong Kyu, Leeuwenburgh Christiaan, Lehti Maarit, Lemieux Helene, Lenaz Giorgio, Lerfall Joergen, Li Pingan Andy, Li Puma Lance, Liang Liping, Liepins Edgars, Lin Chien-Te, Liu Jiankang, Lopez Garcia Luis Carlos, Lucchinetti Eliana, Ma Tao, Macedo Maria Paula, Machado Ivo F, Maciej Sarah, MacMillan-Crow Lee Ann, Magalhaes Jose, Magri Andrea, Majtnerova Pavlina, Makarova Elina, Makrecka-Kuka Marina, Malik Afshan N, Marcouiller Francois, Marechal Amandine, Markova Michaela, Markovic Ivanka, Martin Daniel S, Martins Ana Dias, Martins Joao D, Maseko Tumisang Edward, Maull Felicia, Mazat Jean-Pierre, McKenna Helen T, McKenzie Matthew, McMillan Duncan GG, McStay Gavin P, Mendham Amy, Menze Michael A, Mercer John R, Merz Tamara, Messina Angela, Meszaros Andras, Methner Axel, Michalak Slawomir, Mila Guasch Maria, Minuzzi Luciele M, Misirkic Marjanovic Maja, Moellering Douglas R, Moisoi Nicoleta, Molina Anthony JA, Montaigne David, Moore Anthony L, Moore Christy, Moreau Kerrie, Moreira Bruno P, Moreno-Sanchez Rafael, Mracek Tomas, Muccini Anna Maria, Munro Daniel, Muntane Jordi, Muntean Danina M, Murray Andrew James, Musiol Eva, Nabben Miranda, Nair K Sreekumaran, Nehlin Jan O, Nemec Michal, Nesci Salvatore, Neufer P Darrell, Neuzil Jiri, Neviere Remi, Newsom Sean A, Norman Jennifer, Nozickova Katerina, Nunes Sara, Nuoffer Jean-Marc, O'Brien Kristin, O'Brien Katie A, O'Gorman Donal, Olgar Yusuf, Oliveira Ben, Oliveira Jorge, Oliveira Marcus F, Oliveira Marcos Tulio, Oliveira Pedro Fontes, Oliveira Paulo J, Olsen Rolf Erik, Orynbayeva Zulfiya, Osiewacz Heinz D, Paez Hector, Pak Youngmi Kim, Pallotta Maria Luigia, Palmeira Carlos, Parajuli Nirmala, Passos Joao F, Passrugger Manuela, Patel Hemal H, Pavlova Nadia, Pavlovic Kasja, Pecina Petr, Pedersen Tina M, Perales Jose Carles, Pereira da Silva Grilo da Silva Filomena, Pereira Rita, Pereira Susana P, Perez Valencia Juan Alberto, Perks Kara L, Pesta Dominik, Petit Patrice X, Pettersen Nitschke Ina Katrine, Pichaud Nicolas, Pichler Irene, Piel Sarah, Pietka Terri A, Pinho Sonia A, Pino Maria F, Pirkmajer Sergej, Place Nicolas, Plangger Mario, Porter Craig, Porter Richard K, Preguica Ines, Prigione Alessandro, Procaccio Vincent, Prochownik Edward V, Prola Alexandre, Pulinilkunnil Thomas, Puskarich Michael A, Puurand Marju, Radenkovic Filip, Ramzan Rabia, Rattan Suresh IS, Reano Simone, Reboredo-Rodriguez Patricia, Rees Bernard B, Renner-Sattler Kathrin, Rial Eduardo, Robinson Matthew M, Roden Michael, Rodrigues Ana Sofia, Rodriguez Enrique, Rodriguez-Enriquez Sara, Roesland Gro Vatne, Rohlena Jakub, Rolo Anabela Pinto, Ropelle Eduardo R, Roshanravan Baback, Rossignol Rodrigue, Rossiter Harry B, Rousar Tomas, Rubelj Ivica, Rybacka-Mossakowska Joanna, Saada Reisch Ann, Safaei Zahra, Salin Karine, Salvadego Desy, Sandi Carmen, Saner Nicholas, Santos Diana, Sanz Alberto, Sardao Vilma, Sarlak Saharnaz, Sazanov Leonid A, Scaife Paula, Scatena Roberto, Schartner Melanie, Scheibye-Knudsen Morten, Schilling Jan M, Schlattner Uwe, Schmitt Sabine, Schneider Gasser Edith Mariane, Schoenfeld Peter, Schots Pauke C, Schulz Rainer, Schwarzer Christoph, Scott Graham R, Selman Colin, Sendon Pamella Marie, Shabalina Irina G, Sharma Pushpa, Sharma Vipin, Shevchuk Igor, Shirazi Reza, Shiroma Jonathan G, Siewiera Karolina, Silber Ariel M, Silva Ana Maria, Sims Carrie A, Singer Dominique, Singh Brijesh Kumar, Skolik Robert A, Smenes Benedikte Therese, Smith James, Soares Felix Alexandre Antunes, Sobotka Ondrej, Sokolova Inna, Solesio Maria E, Soliz Jorge, Sommer Natascha, Sonkar Vijay K, Sova Marina, Sowton Alice P, Sparagna Genevieve C, Sparks Lauren M, Spinazzi Marco, Stankova Pavla, Starr Jonathan, Stary Creed, Stefan Eduard, Stelfa Gundega, Stepto Nigel K, Stevanovic Jelena, Stiban Johnny, Stier Antoine, Stocker Roland, Storder Julie, Sumbalova Zuzana, Suomalainen Anu, Suravajhala Prashanth, Svalbe Baiba, Swerdlow Russell H, Swiniuch Daria, Szabo Ildiko, Szewczyk Adam, Szibor Marten, Tanaka Masashi, Tandler Bernard, Tarnopolsky Mark A, Tausan Daniel, Tavernarakis Nektarios, Teodoro Joao Soeiro, Tepp Kersti, Thakkar Himani, Thapa Maheshwor, Thyfault John P, Tomar Dhanendra, Ton Riccardo, Torp May-Kristin, Torres-Quesada Omar, Towheed Atif, Treberg Jason R, Tretter Laszlo, Trewin Adam J, Trifunovic Aleksandra, Trivigno Catherine, Tronstad Karl Johan, Trougakos Ioannis P, Truu Laura, Tuncay Erkan, Turan Belma, Tyrrell Daniel J, Urban Tomas, Urner Sofia, Valentine Joseph Marco, Van Bergen Nicole J, Van der Ende Miranda, Varricchio Frederick, Vaupel Peter, Vella Joanna, Vendelin Marko, Vercesi Anibal E, Verdaguer Ignasi Bofill, Vernerova Andrea, Victor Victor Manuel, Vieira Ligo Teixeira Camila, Vidimce Josif, Viel Christian, Vieyra Adalberto, Vilks Karlis, Villena Josep A, Vincent Vinnyfred, Vinogradov Andrey D, Viscomi Carlo, Vitorino Rui Miguel Pinheiro, Vlachaki Walker Julia, Vogt Sebastian, Volani Chiara, Volska Kristine, Votion Dominique-Marie, Vujacic-Mirski Ksenija, Wagner Brett A, Ward Marie Louise, Warnsmann Verena, Wasserman David H, Watala Cezary, Wei Yau-Huei, Weinberger Klaus M, Weissig Volkmar, White Sarah Haverty, Whitfield Jamie, Wickert Anika, Wieckowski Mariusz R, Wiesner Rudolf J, Williams Caroline M, Winwood-Smith Hugh, Wohlgemuth Stephanie E, Wohlwend Martin, Wolff Jonci Nikolai, Wrutniak-Cabello Chantal, Wuest Rob CI, Yokota Takashi, Zablocki Krzysztof, Zanon Alessandra, Zanou Nadege, Zaugg Kathrin, Zaugg Michael, Zdrazilova Lucie, Zhang Yong, Zhang Yizhu, Zikova Alena, Zischka Hans, Zorzano Antonio, Zujovic Tijana, Zurmanova Jitka, Zvejniece Liga
- Subjects
uncoupling ,MitoPedia: Respiratory states, SI - The International System of Units, IUPAC, Coupling control, Mitochondrial preparations, Protonmotive force, Uncoupling, Oxidative phosphorylation, Phosphorylation efficiency, Electron transfer-pathway, LEAK-respiration, Residual oxygen consumption, Normalization of rate, Flow, Flux, Flux control ratio, Mitochondrial marker, Cell count, Oxygen ,[SDV]Life Sciences [q-bio] ,coupling control ,protonmotive force ,oxidative phosphorylation ,mitochondrial respiratory control ,State 4 ,electron transfer ,State 2 ,State 3 ,Mitochondrial physiology ,residual oxygen consumption ,flux ,normalization ,ion leak and slip compensatory state ,efficiency ,electron transfer system ,flow ,mitochondrial physiology ,oxygen ,mitochondrial preparations ,proton leak - Abstract
As the knowledge base and importance of mitochondrial physiology to evolution, health and diseaseexpands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followthe latest SI guidelines and those of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute BEC 2020.1 doi:10.26124/bec:2020-0001.v1www.bioenergetics-communications.org3of 44to reproducibility between laboratories and thussupport the development of datarepositoriesof mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.
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- 2020
39. Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH
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Simón, Jorge, primary, Goikoetxea-Usandizaga, Naroa, additional, Serrano-Maciá, Marina, additional, Fernández-Ramos, David, additional, Sáenz de Urturi, Diego, additional, Gruskos, Jessica J., additional, Fernández-Tussy, Pablo, additional, Lachiondo-Ortega, Sofía, additional, González-Recio, Irene, additional, Rodríguez-Agudo, Rubén, additional, Gutiérrez-de-Juan, Virginia, additional, Rodríguez-Iruretagoyena, Begoña, additional, Varela-Rey, Marta, additional, Gimenez-Mascarell, Paula, additional, Mercado-Gomez, María, additional, Gómez-Santos, Beatriz, additional, Fernandez-Rodriguez, Carmen, additional, Lopitz-Otsoa, Fernando, additional, Bizkarguenaga, Maider, additional, Dames, Sibylle, additional, Schaeper, Ute, additional, Martin, Franz, additional, Sabio, Guadalupe, additional, Iruzubieta, Paula, additional, Crespo, Javier, additional, Aspichueta, Patricia, additional, Chu, Kevan H.-Y., additional, Buccella, Daniela, additional, Martín, César, additional, Delgado, Teresa Cardoso, additional, Martínez-Cruz, Luis Alfonso, additional, and Martínez-Chantar, María Luz, additional
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- 2021
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40. Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity
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Medicina, Medikuntza, Fernández Tussy, Pablo, Rodríguez Agudo, Rubén, Fernández Ramos, David, Barbier Torres, Lucía, Zubiete Franco, Imanol, López de Davalillo, Sergio, Herráez Aguilar, Elisa, Goikoetxea Usandizaga, Naroa, Lachiondo Ortega, Sofía, Simón Espinosa, Jorge, Lopitz Otsoa, Fernando, Gutiérrez de Juan, Virginia, McCain, Misti V., Perugorria Montiel, María Jesús, Mabe Alvarez, Jon, Navasa, Nicolás, Rodrigues, Cecilia M. P., Fabregat, Isabel, Boix, Loreto, Sapena, Victor, Anguita Castillo, Juan de Dios, Lu, Shelly C., Mato de la Paz, José María, Bañales Asurmendi, Jesús María, Villa, Erica, Reeves, Helen L., Bruix, Jordi, Reig, María, Marín, José J. G., Cardoso Delgado, Teresa de Jesús, Martínez Chantar, María Luz, Medicina, Medikuntza, Fernández Tussy, Pablo, Rodríguez Agudo, Rubén, Fernández Ramos, David, Barbier Torres, Lucía, Zubiete Franco, Imanol, López de Davalillo, Sergio, Herráez Aguilar, Elisa, Goikoetxea Usandizaga, Naroa, Lachiondo Ortega, Sofía, Simón Espinosa, Jorge, Lopitz Otsoa, Fernando, Gutiérrez de Juan, Virginia, McCain, Misti V., Perugorria Montiel, María Jesús, Mabe Alvarez, Jon, Navasa, Nicolás, Rodrigues, Cecilia M. P., Fabregat, Isabel, Boix, Loreto, Sapena, Victor, Anguita Castillo, Juan de Dios, Lu, Shelly C., Mato de la Paz, José María, Bañales Asurmendi, Jesús María, Villa, Erica, Reeves, Helen L., Bruix, Jordi, Reig, María, Marín, José J. G., Cardoso Delgado, Teresa de Jesús, and Martínez Chantar, María Luz
- Abstract
Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n=16 and n=20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n=100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n=16) and in an additional cohort of tumor/non-tumor paired samples (n=20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.
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- 2021
41. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via DEPTOR-mTOR axis
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Bioquímica y biología molecular, Filosofía, Biokimika eta biologia molekularra, Fisiologia, Serrano Maciá, Marina, Simon, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea Usandizaga, Naroa, Lopitz Otsoa, Fernando, Saenz de Urturi Indart, Diego, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga, Maider, Fernández Ramos, David, Buqué García, Xabier, Baselli, Guido A., Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Bañales Asurmendi, Jesús María, Avila, Matias A., Marin, José J. G., Aspichueta Celaá, Patricia, Sutherland, James D., Barrio Olano, María Rosa, Mayor Martínez, Ugo, Elortza, Felix, Xirodimas, Dimitri, Nogueiras Pozo, Rubén, Delgado, Teresa C., Martínez Chantar, María Luz, Bioquímica y biología molecular, Filosofía, Biokimika eta biologia molekularra, Fisiologia, Serrano Maciá, Marina, Simon, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea Usandizaga, Naroa, Lopitz Otsoa, Fernando, Saenz de Urturi Indart, Diego, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga, Maider, Fernández Ramos, David, Buqué García, Xabier, Baselli, Guido A., Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Bañales Asurmendi, Jesús María, Avila, Matias A., Marin, José J. G., Aspichueta Celaá, Patricia, Sutherland, James D., Barrio Olano, María Rosa, Mayor Martínez, Ugo, Elortza, Felix, Xirodimas, Dimitri, Nogueiras Pozo, Rubén, Delgado, Teresa C., and Martínez Chantar, María Luz
- Abstract
[EN] Objective: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Methods: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. Results: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models
- Published
- 2021
42. Magnesium Accumulation Upon Cyclin M4 Silencing Activates Microsomal Triglyceride Transfer Protein Improving NASH
- Author
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Bioquímica y biología molecular, Fisiología, Biokimika eta biologia molekularra, Fisiologia, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Fernández Ramos, David, Sáenz de Urturi Indart, Diego, Gruskos, Jessica J., Fernández Tussy, Pablo, Lachiondo Ortega, Sofía, González Recio, Irene, Rodríguez Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez Iruretagoyena, Begoña, Varela Rey, Marta, Giménez Mascarell, Paula, Mercado Gómez, María, Gómez Santos, Beatriz, Fernández Rodríguez, Carmen, Lopitz Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martin, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta Celaá, Patricia, Chu, Kevan H. Y., Buccella, Daniela, Martín Plágaro, César Augusto, Cardoso Delgado, Teresa de Jesús, Martínez de la Cruz, Alfonso, Martínez Chantar, María Luz, Bioquímica y biología molecular, Fisiología, Biokimika eta biologia molekularra, Fisiologia, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Fernández Ramos, David, Sáenz de Urturi Indart, Diego, Gruskos, Jessica J., Fernández Tussy, Pablo, Lachiondo Ortega, Sofía, González Recio, Irene, Rodríguez Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez Iruretagoyena, Begoña, Varela Rey, Marta, Giménez Mascarell, Paula, Mercado Gómez, María, Gómez Santos, Beatriz, Fernández Rodríguez, Carmen, Lopitz Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martin, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta Celaá, Patricia, Chu, Kevan H. Y., Buccella, Daniela, Martín Plágaro, César Augusto, Cardoso Delgado, Teresa de Jesús, Martínez de la Cruz, Alfonso, and Martínez Chantar, María Luz
- Abstract
Background & Aims: Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Methods: Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine (R) or conjugated to N-acetylgalactosamine. Results: Patients with NASH showed hepatic CNNM4 over-expression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. Conclusions: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. Lay summary: Cyclin M4 (CNNM4) is overexpressed in nonalcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.
- Published
- 2021
43. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis
- Author
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Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Serrano Maciá, Marina, Simón, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea-Usandizaga, Naroa, Lopitz Otsoa, Fernando, Sáenz de Urturi, Diego, Rodríguez Agudo, Rubén, Lachiondo-Ortega, Sofia, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga-Uribiarte, Maider, Fernández-Ramos, David, Buqué, Xabier, Baselli, Guido Alessandro, Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Banales, Jesus, Avila, Matias A., Marin, Jose, Aspichueta, Patricia, Sutherland, James D., Barrio, Rosa, Mayor, Ugo, Elortza, Felix, Xirodimas, Dimitris, Nogueiras Pozo, Rubén, Delgado, Teresa, Martinez Chantar, Maria Luz, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Serrano Maciá, Marina, Simón, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea-Usandizaga, Naroa, Lopitz Otsoa, Fernando, Sáenz de Urturi, Diego, Rodríguez Agudo, Rubén, Lachiondo-Ortega, Sofia, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga-Uribiarte, Maider, Fernández-Ramos, David, Buqué, Xabier, Baselli, Guido Alessandro, Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Banales, Jesus, Avila, Matias A., Marin, Jose, Aspichueta, Patricia, Sutherland, James D., Barrio, Rosa, Mayor, Ugo, Elortza, Felix, Xirodimas, Dimitris, Nogueiras Pozo, Rubén, Delgado, Teresa, and Martinez Chantar, Maria Luz
- Abstract
Objective: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Methods: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. Results: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models. Conclusions: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD
- Published
- 2021
44. E2F1 and E2F2-mediated repression of CPT2 establishes a lipid-rich tumor-promoting environment
- Author
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Gonzalez-Romero, Francisco, Mestre, Daniela, Aurrekoetxea, Igor, O'Rourke, Colm J., Andersen, Jesper B., Woodhoo, Ashwin, Tamayo-Caro, Miguel, Varela-Rey, Marta, Palomo-Irigoyen, Marta, Gomez-Santos, Beatriz, de Urturi, Diego Saenz, Nuñez-García, Maitane, García-Rodríguez, Juan L., Fernandez-Ares, Larraitz, Buque, Xabier, Iglesias-Ara, Ainhoa, Bernales, Irantzu, de Juan, Virginia Gutierrez, Delgado, Teresa C., Goikoetxea-Usandizaga, Naroa, Lee, Richard, Bhanot, Sanjay, Delgado, Igotz, Perugorria, Maria J., Errazti, Gaizka, Mosteiro, Lorena, Gaztambide, Sonia, de la Piscina, Idoia Martinez, Iruzubieta, Paula, Crespo, Javier, Banales, Jesus M., Martínez-Chantar, Maria L., Castaño, Luis, Zubiaga, Ana M., Aspichueta, Patricia, Gonzalez-Romero, Francisco, Mestre, Daniela, Aurrekoetxea, Igor, O'Rourke, Colm J., Andersen, Jesper B., Woodhoo, Ashwin, Tamayo-Caro, Miguel, Varela-Rey, Marta, Palomo-Irigoyen, Marta, Gomez-Santos, Beatriz, de Urturi, Diego Saenz, Nuñez-García, Maitane, García-Rodríguez, Juan L., Fernandez-Ares, Larraitz, Buque, Xabier, Iglesias-Ara, Ainhoa, Bernales, Irantzu, de Juan, Virginia Gutierrez, Delgado, Teresa C., Goikoetxea-Usandizaga, Naroa, Lee, Richard, Bhanot, Sanjay, Delgado, Igotz, Perugorria, Maria J., Errazti, Gaizka, Mosteiro, Lorena, Gaztambide, Sonia, de la Piscina, Idoia Martinez, Iruzubieta, Paula, Crespo, Javier, Banales, Jesus M., Martínez-Chantar, Maria L., Castaño, Luis, Zubiaga, Ana M., and Aspichueta, Patricia
- Abstract
Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1-/- and E2f2-/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1-/- and E2f2-/- mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis.
- Published
- 2021
45. Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Eusko Jaurlaritza, European Commission, Fundación Vasca de Innovación e Investigación Sanitarias, Radio Televisión Pública Vasca, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Ministerio de Economía y Competitividad (España), National Institutes of Health (US), Junta de Andalucía, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernández-Rodríguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martín, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Cardoso Delgado, Teresa de Jesús, Martínez-Cruz, Luis Alfonso, Martínez-Chantar, María Luz, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Eusko Jaurlaritza, European Commission, Fundación Vasca de Innovación e Investigación Sanitarias, Radio Televisión Pública Vasca, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Ministerio de Economía y Competitividad (España), National Institutes of Health (US), Junta de Andalucía, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernández-Rodríguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martín, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Cardoso Delgado, Teresa de Jesús, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, María Luz
- Abstract
Background & Aims: Perturbations of intracellular magnesium (Mg) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Methods: Serum Mg levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. Results: Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. Conclusions: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. Lay summary: Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.
- Published
- 2021
46. E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
- Author
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González-Romero, Francisco, primary, Mestre, Daniela, additional, Aurrekoetxea, Igor, additional, O'Rourke, Colm J., additional, Andersen, Jesper B., additional, Woodhoo, Ashwin, additional, Tamayo-Caro, Miguel, additional, Varela-Rey, Marta, additional, Palomo-Irigoyen, Marta, additional, Gómez-Santos, Beatriz, additional, de Urturi, Diego Sáenz, additional, Núñez-García, Maitane, additional, García-Rodríguez, Juan L., additional, Fernández-Ares, Larraitz, additional, Buqué, Xabier, additional, Iglesias-Ara, Ainhoa, additional, Bernales, Irantzu, additional, De Juan, Virginia Gutierrez, additional, Delgado, Teresa C., additional, Goikoetxea-Usandizaga, Naroa, additional, Lee, Richard, additional, Bhanot, Sanjay, additional, Delgado, Igotz, additional, Perugorria, Maria J., additional, Errazti, Gaizka, additional, Mosteiro, Lorena, additional, Gaztambide, Sonia, additional, Martinez de la Piscina, Idoia, additional, Iruzubieta, Paula, additional, Crespo, Javier, additional, Banales, Jesus M., additional, Martínez-Chantar, Maria L., additional, Castaño, Luis, additional, Zubiaga, Ana M., additional, and Aspichueta, Patricia, additional
- Published
- 2021
- Full Text
- View/download PDF
47. Nutraceutical Properties of Polyphenols against Liver Diseases
- Author
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Biología celular e histología, Zelulen biologia eta histologia, Simón Espinosa, Jorge, Casado Andrés, María del Rosario, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Martínez Chantar, María Luz, Biología celular e histología, Zelulen biologia eta histologia, Simón Espinosa, Jorge, Casado Andrés, María del Rosario, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, and Martínez Chantar, María Luz
- Abstract
Current food tendencies, suboptimal dietary habits and a sedentary lifestyle are spreading metabolic disorders worldwide. Consequently, the prevalence of liver pathologies is increasing, as it is the main metabolic organ in the body. Chronic liver diseases, with non-alcoholic fatty liver disease (NAFLD) as the main cause, have an alarming prevalence of around 25% worldwide. Otherwise, the consumption of certain drugs leads to an acute liver failure (ALF), with drug-induced liver injury (DILI) as its main cause, or alcoholic liver disease (ALD). Although programs carried out by authorities are focused on improving dietary habits and lifestyle, the long-term compliance of the patient makes them difficult to follow. Thus, the supplementation with certain substances may represent a more easy-to-follow approach for patients. In this context, the consumption of polyphenol-rich food represents an attractive alternative as these compounds have been characterized to be effective in ameliorating liver pathologies. Despite of their structural diversity, certain similar characteristics allow to classify polyphenols in 5 groups: stilbenes, flavonoids, phenolic acids, lignans and curcuminoids. Herein, we have identified the most relevant compounds in each group and characterized their main sources. By this, authorities should encourage the consumption of polyphenol-rich products, as most of them are available in quotidian life, which might reduce the socioeconomical burden of liver diseases.
- Published
- 2020
48. Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis
- Author
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Bioquímica y biología molecular, Biokimika eta biologia molekularra, Mercado Gómez, María, Lopitz Otsoa, Fernando, Azkargorta, Mikel, Serrano Maciá, Marina, Lachiondo Ortega, Sofía, Goikoetxea Usandizaga, Naroa, Rodríguez Agudo, Rubén, Fernández Ramos, David, Bizkarguenaga, Maider, Gutiérrez de Juan, Virginia, Lectez, Benoit, Aloria Escolastico, Kerman, Arizmendi Bastarrika, Jesús María, Simón Espinosa, Jorge, Alonso, Cristina, Lozano, Juan José, Avila, Matias A., Bañales Asurmendi, Jesús María, Marin, Jose J. G., Beraza, Naiara, Mato, José M., Elortza, Felix, Barrio Olano, María Rosa, Sutherland, James D., Mayor Martínez, Ugo, Martínez Chantar, María Luz, Cardoso Delgado, Teresa de Jesús, Bioquímica y biología molecular, Biokimika eta biologia molekularra, Mercado Gómez, María, Lopitz Otsoa, Fernando, Azkargorta, Mikel, Serrano Maciá, Marina, Lachiondo Ortega, Sofía, Goikoetxea Usandizaga, Naroa, Rodríguez Agudo, Rubén, Fernández Ramos, David, Bizkarguenaga, Maider, Gutiérrez de Juan, Virginia, Lectez, Benoit, Aloria Escolastico, Kerman, Arizmendi Bastarrika, Jesús María, Simón Espinosa, Jorge, Alonso, Cristina, Lozano, Juan José, Avila, Matias A., Bañales Asurmendi, Jesús María, Marin, Jose J. G., Beraza, Naiara, Mato, José M., Elortza, Felix, Barrio Olano, María Rosa, Sutherland, James D., Mayor Martínez, Ugo, Martínez Chantar, María Luz, and Cardoso Delgado, Teresa de Jesús
- Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.
- Published
- 2020
49. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals.
- Author
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Goikoetxea‐Usandizaga, Naroa, Serrano‐Maciá, Marina, Delgado, Teresa C., Simón, Jorge, Fernández Ramos, David, Barriales, Diego, Cornide, Maria E., Jiménez, Mónica, Pérez‐Redondo, Marina, Lachiondo‐Ortega, Sofia, Rodríguez‐Agudo, Rubén, Bizkarguenaga, Maider, Zalamea, Juan Diego, Pasco, Samuel T., Caballero‐Díaz, Daniel, Alfano, Benedetta, Bravo, Miren, González‐Recio, Irene, Mercado‐Gómez, Maria, and Gil‐Pitarch, Clàudia
- Published
- 2022
- Full Text
- View/download PDF
50. Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis
- Author
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Mercado-Gómez, Maria, primary, Lopitz-Otsoa, Fernando, additional, Azkargorta, Mikel, additional, Serrano-Maciá, Marina, additional, Lachiondo-Ortega, Sofia, additional, Goikoetxea-Usandizaga, Naroa, additional, Rodríguez-Agudo, Rubén, additional, Fernández-Ramos, David, additional, Bizkarguenaga, Maider, additional, Juan, Virginia Gutiérrez-de, additional, Lectez, Benoît, additional, Aloria, Kerman, additional, Arizmendi, Jesus M., additional, Simon, Jorge, additional, Alonso, Cristina, additional, Lozano, Juan J., additional, Avila, Matias A., additional, Banales, Jesus M., additional, Marin, Jose J. G., additional, Beraza, Naiara, additional, Mato, José M., additional, Elortza, Félix, additional, Barrio, Rosa, additional, Sutherland, James D., additional, Mayor, Ugo, additional, Martínez-Chantar, María L., additional, and Delgado, Teresa C., additional
- Published
- 2020
- Full Text
- View/download PDF
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