RESEARCH INTEREST
1. Role of the mitochondrial sodium/calcium exchanger NCLX in oxidative damage and ferroptotic cell death in stroke.
We discovered the mechanism by which mitochondrial Na+ import via NCLX disrupts the mitochondrial electron transport chain, inducing the production of superoxide and reactive oxygen species (ROS) during acute hypoxia. Our current work investigates the role of NCLX and the molecular mechanisms in which it participates in different pathophysiological settings, and we also evaluate the pharmacological application of new NCLX inhibitors in related diseases.
In this line of research, we focus on the role of NCLX in oxidative damage during stroke, using cell cultures and animal models of stroke, as well as observational clinical studies. We investigate various aspects of this role, including the mechanisms of ROS generation and ferroptosis, a recently described form of cell death induced by iron dysregulation and oxidative lipid damage.
2. Role of the mitochondrial sodium/calcium exchanger NCLX in inflammation and immunity. Sodium dysregulation is implicated in various inflammatory pathways and immune system dysfunctions. In this line of research, we are currently studying the role of NCLX in the activation of the NLRP3 inflammasome, as well as the potential pharmacological use of NCLX inhibitors in diseases where this inflammatory pathway plays a significant role, particularly gout and stroke.
3. Protein sulfhydration in neurological development in Down syndrome.
We have previously studied the functional role of S-nitrosylation and developed redox proteomics methods to detect oxidative post-translational modifications of cysteine, which we have applied to the study of neurogenesis and other pathophysiological settings. In an international collaborative project, we are currently studying the role of protein sulfhydration (an oxidative modification of cysteines induced by the gas transmitter hydrogen sulfide, H2S) in neurogenesis in Down syndrome.
El intercambiador mitocondrial de sodio/calcio NCLX como diana farmacológica en ictus isquémico. Proyecto asociado. PDC2022-133246-I00. ISCIII. 2022-2024.
Los proyectos PDC2022, están financiados por MCIN/AEI/10.13039/ 501100011033 y por la Unión Europea-NextGenerationEU/PRTR.
Dissecting the role of mitochondrial Na+/Ca2+/Li+ exchanger NCLX and reactive oxygen species in stroke and inflammation. PID2021-124688OB-I00. ISCIII. 2022-2024.
Las ayudas objeto de esta convocatoria corresponden a actuaciones del Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023 (en adelante, Plan Estatal), integrado en la Estrategia Española de Ciencia, Tecnología e Innovación 2021-2027 y aprobado por Acuerdo del Consejo de Ministros en su reunión de 15 de junio de 2021. Esta convocatoria forma parte del Programa Estatal para Impulsar la Investigación Científico-Técnica y su Transferencia. Cofinanciado por la Unión Europea.
Implicaciones de la hipoxia y las especies reactivas de oxígeno en las enfermedades neurodegenerativas. Fundación Domingo Martínez. 2014-2015.
Modificaciones postraduccionales oxidativas en fisiopatología molecular. PI12/00875. ISCIII. 2013-2015.
Señalización en hipoxia por especies reactivas de oxígeno, y proteómica redox: de los mecanismos moleculares a las aplicaciones clínicas. PI15/00107. ISCIII. 2016-2018.
Hernansanz-Agustín P, Izquierdo-Álvarez A, Sánchez-Gómez FJ, Ramos E, Villa-Piña T, Lamas S, Bogdanova A, Martínez-Ruiz A. Acute hypoxia produces a superoxide burst in cells. Free Radic Biol Med 2014. 71: 146-156. FI: 5,736(Q1). PMID: 24637263. DOI: 10.1016/j.freeradbiomed.2014.03.011.
Hernansanz-Agustín P, Izquierdo-Álvarez A, García-Ortiz A, Ibiza S, Serrador JM, Martínez-Ruiz A. Nitrosothiols in the Immune System: Signaling and Protection. Antioxid. Redox Signal. 2013. 18: 288-308. FI: 7,667(Q1). PMID: 22746191. DOI: 10.1089/ars.2012.4765.
Martínez-Ruiz A, Araújo IM, Izquierdo-Álvarez A, Hernansanz-Agustín P, Lamas S, Serrador JM. Specificity in S-Nitrosylation: A Short-Range Mechanism for NO Signaling?. Antioxid. Redox Signal. 2013. 19: 1220-1235. FI: 7,667(Q1). PMID: 23157283. DOI: 10.1089/ars.2012.5066.
Izquierdo-Álvarez A, Ramos E, Villanueva J, Hernansanz-Agustín P, Fernández-Rodríguez R, Tello D, Carrascal M, Martínez-Ruiz A. Differential redox proteomics allows identification of proteins reversibly oxidized at cysteine residues in endothelial cells in response to acute hypoxia. J Proteomics 2012. 75: 5449-5462. FI: 4,088(Q1). PMID: 22800641. DOI: 10.1016/j.jprot.2012.06.035.
Izquierdo-Alvarez, Alicia, Martinez-Ruiz, Antonio. Thiol redox proteomics seen with fluorescent eyes: The detection of cysteine oxidative modifications by fluorescence derivatization and 2-DE. J Proteomics 2011. 75: 329-338. FI: 4,878(Q1). PMID: 21983555. DOI: 10.1016/j.jprot.2011.09.013.
