Person:
Martínez Ruiz, Antonio

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First Name
Antonio
Last Name
Martínez Ruiz
URI
https://hdl.handle.net/20.500.14352/77617
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
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2020 - 20232
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    Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling
    (Nature (London), 2020) Hernansanz Agustín, Pablo; Choya Foces, Carmen; Carregal Romero, Susana; Ramos, Elena; Oliva, Tamara; Villa Piña, Tamara; Moreno, Laura; Izquierdo Alvarez, Alicia; Cabrera Garcia, J.Daniel; Cortés, Ana; Lechuga Vieco, Ana Victoria; Jadiya, Pooja; Navarro, Elisa; Parada, Esther; Palomino Antolín, Alejandra; Tello, Daniel; Acín Pérez, Rebeca; Rodríguez Aguilera, Juan Carlos; Navas, Plácido; Cogolludo, Angel; López Montero, Iván; Martínez del Pozo, Álvaro; Egea, Javier; López, Manuela G.; Elrod, John W.; Ruiz Cabello, J.; Bogdanova, Anna; Enríquez, José Antonio; Martínez Ruiz, Antonio
    All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism.
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    Regulation of Ras Signaling by S-Nitrosylation
    (Antioxidants, 2023) Simão, Sónia; Agostinho, Rafaela Ribeiro; Martínez Ruiz, Antonio; Araújo, Inês Maria
    Ras are a family of small GTPases that function as signal transduction mediators and are involved in cell proliferation, migration, differentiation and survival. The significance of Ras is further evidenced by the fact that Ras genes are among the most mutated oncogenes in different types of cancers. After translation, Ras proteins can be targets of post-translational modifications (PTM), which can alter the intracellular dynamics of the protein. In this review, we will focus on how S-nitrosylation of Ras affects the way these proteins interact with membranes, its cellular localization, and its activity. S-Nitrosylation occurs when a nitrosyl moiety of nitric oxide (NO) is covalently attached to a thiol group of a cysteine residue in a target protein. In Ras, the conserved Cys118 is the most surface-exposed Cys and the preferable residue for NO action, leading to the initiation of transduction events. Ras transduces the mitogen-activated protein kinases (MAPK), the phosphoinositide-3 kinase (PI3K) and the RalGEF cellular pathways. S-Nitrosylation of elements of the RalGEF cascade remains to be identified. On the contrary, it is well established that several components of the MAPK and PI3K pathways, as well as different proteins associated with these cascades, can be modified by S-nitrosylation. Overall, this review presents a better understanding of Ras S-nitrosylation, increasing the knowledge on the dynamics of these proteins in the presence of NO and the underlying implications in cellular signaling