Referencia

Bermúdez-Muñoz, J.M., Celaya, A.M., Hijazo-Pechero, S., Wang, J., Serrano, M. and Varela-Nieto, I. (2020), G6PD overexpression protects from oxidative stress and age-related hearing loss. Aging Cell, 19: e13275. https://doi.org/10.1111/acel.13275
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Autores

Jose M. Bermúdez-Muñoz, Adelaida M. Celaya, Sara Hijazo-Pechero, Jing Wang, Manuel Serrano, Isabel Varela-Nieto

Resumen

Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the rate-limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice (G6PD-Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild-type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3-month-old G6PD-Tg mice than in wild-type counterparts, whereas the levels of pro-apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL+ apoptotic cells were all lower in 9-month-old G6PD-Tg than in wild-type counterparts. Unexpectedly, G6PD overexpression triggered low-grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression.

Descripción

Nuestra investigación pone de manifiesto por primera vez el impacto de incrementar la actividad de la enzima G6PD en la homeostasis redox coclear. A través de un modelo murino de ganancia de función, demostramos que la sobrexpresión de esta enzima limita la producción de especies reactivas del oxígeno y protege del daño oxidativo en la cóclea, retrasando así la progresión de la pérdida auditiva asociada a la edad. Estos resultados abren una nueva vía para una potencial terapia para la presbiacusia basada en el mantenimiento de los niveles de NADPH con la edad.

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REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de neurobiología de la audición liderado por la profesora de investigación Isabel Varela Nieto tiene como principal objetivo el estudio de la fisiopatología de la pérdida auditiva. En particular, estamos interesados en las bases genéticas y moleculares de la pérdida de audición de diferente etiología, así como en la identificación de nuevas dianas terapéuticas y biomarcadores de progresión de la hipoacusia. Conjuntamente, llevamos a cabo ensayos preclínicos de nuevas terapias con pequeñas moléculas en modelos animales y líneas celulares de sordera neurosensorial además de co-terapias para el implante coclear.

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