RESEARCH INTEREST
Insufficient oxygen supply (hypoxia) is a hallmark of numerous life-threatening conditions with unmet medical needs, such as solid tumor growth, chronic obstructive pulmonary disease (COPD), ischemic diseases, and obesity. Cells are equipped with oxygen-sensing systems to mount a programmed response when oxygen becomes limited. Hypoxia-inducible factors (HIF1, HIF2, and HIF3) are central regulators of this cellular response to oxygen fluctuations. Our current research focus is on the role of HIF oxygen-sensing pathways in cancer, lung diseases, liver regeneration, anemia, and pericyte biology. In particular, we are primarily interested in cellular metabolic reprogramming, which is one of the central biological functions carried out by HIF factors. 1) HIF factors and renal cell carcinoma: clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is characterized by the constitutive activation of HIF factors.
We have identified new metabolic responses (mitochondrial rewiring and amino acid metabolism) mediated by HIF1 or HIF2, which are essential for understanding the progression of these tumors and may also be relevant in other tumor types (Elorza et al. Molecular Cell 2012; Meléndez Rodríguez et al. Cell Reports 2019; Urrutia et al. Cell Reports 2024). We are currently investigating new mitochondria-dependent signals, not only in ccRCC but also in other hypoxic settings. 2) HIF factors and airway dysfunction in lung diseases: Lung diseases, such as chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome (SAHS), are the most common respiratory diseases causing morbidity and mortality, and are projected to be the third leading cause of death worldwide by 2020. They are characterized by insufficient oxygen levels in the blood (hypoxemia)—continuous in COPD and intermittent in SASH—and are associated with pulmonary oxidative damage and an exaggerated inflammatory response in the lung and throughout the body. Surprisingly, the bronchial epithelium is the first group of cells to come into contact with oxygen, yet the role of HIF factors remains largely unknown.
We have previously demonstrated that the HIF2 isoform plays a central role in the bronchial epithelium’s response to hypoxia (Elorza et al. Molecular Cell 2012; Torres-Capelli et al. Scientific Reports 2016). More recently, we have generated gain-of-function and loss-of-function models of HIF factors in the bronchial epithelium to study their role in lung biology. 3). The role of HIF factors in liver regeneration following hepatectomy, taking into account the role of HIF factors (HIF2a) in the metabolism of essential and non-essential amino acids. 4) Furthermore, we are interested in kidney diseases and anemia, a pathological scenario in which hypoxia and HIF factors are activated as a compensatory response to increase erythropoietin (EPO) production in renal cells. In this vein, the group has previously published on the biology of EPO (Bouthelier et al. iScience 2023; Urrutia et al. Acta Physiologica 2021). The group is interested in the molecular and epigenetic mechanisms that may compromise EPO production, the primary cause of anemia associated with chronic kidney disease. 5).
Finally, the group is interested in the role of HIF and its impact on metabolism in pericyte and vascular dysfunction. In this context, the group has recently identified the mitochondrial regulator NDUFA4L2 (an HIF target) as a marker for pericytes (Mesa Ciller et al. J Cereb Blood Flow Metab. 2022).
Potentiation of mitochondrial activity in adipose tissue as therapeutical strategy for obesity and type 2 diabetes: interplay between oxygen sensing and neuregulin signaling. 534/C/2016. Marató TV3. 2016-2019.
Papel de los factores de respuesta a oxigeno HIF en patología pulmonar y biomarcadores diagnostico/pronostico no invasivos en enfermedad respiratoria. SAF2013-46058-R. MINECO. 2014-2016.
CONSEPOC: Inflamación e hipoxia: mecanismos en desarrollo y progresión en EPOC y SAHS. S2010/BMD-2542. CAM. 2012-2015.
RECAVA: Red de Investigación Cardiovascular. RD12/0042/0065. ISCIII. 2013-2016.
Inflamación e hipoxia: mecanismos en desarrollo y progresión en EPOC y SAHS. S2010/BMD-2542. CAM. 2012-2015.
Elorza, Ainara, Soro-Arnaiz, Ines, Melendez-Rodriguez, Florinda, Rodriguez-Vaello, Victoria, Marsboom, Glenn, de Carcer, Guillermo, Acosta-Iborra, Barbara, Albacete-Albacete, Lucas, Ordonez, Angel, Serrano-Oviedo, Leticia, Miguel Gimenez-Bachs, Jose, Vara-Vega, Alicia, Salinas, Antonio, Sanchez-Prieto, Ricardo, Martin del Rio, Rafael, Sanchez-Madrid, Francisco, Malumbres, Marcos, Landazuri, Manuel O., Aragones, Julian. HIF2 alpha Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5. Mol. Cell 2012. 48: 681-691. FI: 15,280(Q1). PMID: 23103253. DOI: 10.1016/j.molcel.2012.09.017.
Palazón A, Martínez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, Sanmamed MF, Perez-Gracia JL, Peñuelas I, Hervás-Stubbs S, Rouzaut A, de Landázuri MO, Jure-Kunkel M, Aragonés J, Melero I. The HIF-1 alpha Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy. Cancer Discov. 2012. 2: 608-623. FI: 10,143(Q1). PMID: 22719018. DOI: 10.1158/2159-8290.CD-11-0314.
Tello, Daniel, Balsa, Eduardo, Acosta-Iborra, Barbara, Fuertes-Yebra, Esther, Elorza, Ainara, Ordonez, Angel, Corral-Escariz, Maria, Soro, Ines, Lopez-Bernardo, Elia, Perales-Clemente, Ester, Martinez-Ruiz, Antonio, Antonio Enriquez, Jose, Aragones, Julian, Cadenas, Susana, Landazuri, Manuel O. Induction of the Mitochondrial NDUFA4L2 Protein by HIF-1 alpha Decreases Oxygen Consumption by Inhibiting Complex I Activity. Cell Metab 2011. 14: 768-779. FI: 13,668(Q1). PMID: 22100406. DOI: 10.1016/j.cmet.2011.10.008.
Miro-Murillo, Marta, Elorza, Ainara, Soro-Arnaiz, Ines, Albacete-Albacete, Lucas, Ordonez, Angel, Balsa, Eduardo, Vara-Vega, Alicia, Vazquez, Silvia, Fuertes, Esther, Fernandez-Criado, Carmen, Landazuri, Manuel O., Aragones, Julian. Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression. PLoS One 2011. FI: 4,092(Q1). PMID: 21811636. DOI: 10.1371/journal.pone.0022589.
Schneider M, Van Geyte K, Fraisl P, Kiss J, Aragonés J, Mazzone M, Mairbäurl H, De Bock K, Jeoung NH, Mollenhauer M, Georgiadou M, Bishop T, Roncal C, Sutherland A, Jordan B, Gallez B, Weitz J, Harris RA, Maxwell P, Baes M, Ratcliffe P, Carmeliet P. Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. Gastroenterology 2010. 138: 1143-438. FI: 12,032(Q1). PMID: 19818783. DOI: 10.1053/j.gastro.2009.09.057.
