Referencia

Nature Communications (2012). 3:718 (doi:10.1038/ncomms17229)

Autores

Quintana-Cabrera, R.; Fernández-Fernández, S.; Bobo-Jiménez, V.; Escobar, J.; Sastre, J; Almeida, A.; Bolaños, J.P.

Resumen

Reactive oxygen species regulate redox-signaling processes, but in excess they can cause cell damage, hence underlying the aetiology of several neurological diseases. Through its ability to down modulate reactive oxygen species, glutathione is considered an essential thiol-antioxidant derivative, yet under certain circumstances it is dispensable for cell growth and redox control. Here we show, by directing the biosynthesis of γ-glutamylcysteine—the immediate glutathione precursor—to mitochondria, that it effciently detoxifes hydrogen peroxide and superoxide anion, regardless of cellular glutathione concentrations. Knocking down glutathione peroxidase-1 drastically increases superoxide anion in cells synthesizing mitochondrial γ-glutamylcysteine. In vitro, γ-glutamylcysteine is as effcient as glutathione in disposing of hydrogen peroxide by glutathione peroxidase-1. In primary neurons, endogenously synthesized γ-glutamylcysteine fully prevents apoptotic death in several neurotoxic paradigms and, in an in vivo mouse model of neurodegeneration, γ-glutamylcysteine protects against neuronal loss and motor impairment. Thus, γ-glutamylcysteine takes over the antioxidant and neuroprotective functions of glutathione by acting as glutathione peroxidase-1 cofactor.

Descripción

El tripéptido glutatión se considera el principal antioxidante tiólico, y numerosos estudios han demostrado que es esencial para la supervivencia celular. En este trabajo, dirigiendo a la mitocondria la biosíntesis de su precursor γ-glutamilcisteína, demostramos que las funciones antioxidantes del glutatión las asume γ-glutamilcisteína al actuar como cofactor de la glutatión peroxidasa-1. Así, γ-glutamilcisteína elimina eficazmente las especies reactivas de oxígeno, previniendo la pérdida neuronal y la descoordinación motora en un modelo de neurodegeneración in vivo.

imagen mayo

REFERENCIA DEL GRUPO INVESTIGADOR

Rubén Quintana Cabrera realizó su tesis doctoral en la Universidad de Salamanca bajo la dirección conjunta de Juan P. Bolaños y Ángeles Almeida. Una de las principales líneas de investigación del grupo de Bolaños consiste en conocer mejor los mecanismos de control de la bioenergética y respuesta neuronal al estrés oxidativo. En los últimos años, nuestro trabajo ha contribuido a explicar algunos de los mecanismos que regulan estos procesos, así como su implicación en patologías neurodegenerativas.

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