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
Portada revista 002

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.

Foto grupo 002

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.

Leer más

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

25-04-2021

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO)...

Leer más

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development

29-03-2021

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found...

Leer más

Ceramide chain length–dependent protein sorting into selective endoplasmic reticulum exit sites

22-02-2021

Protein sorting in the secretory pathway is crucial to maintain cellular compartmentalization and homeostasis. In addition to coat-mediated sorting, the role of lipids in driving protein sorting during secretory transport...

Leer más

Antigen retrieval and clearing for whole-organ immunofluorescence by FLASH

25-01-2021

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment...

Leer más

Viral Bcl2s' transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

08-01-2021

Viral control of programmed cell death relies in part on the expression of viral analogs of the B-cell lymphoma 2 (Bcl2) protein known as viral Bcl2s (vBcl2s). vBcl2s control apoptosis...

Leer más

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFß after myocardial infarction

01-12-2020

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood...

Leer más

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

30-10-2020

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic...

Leer más

Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

01-10-2020

C3G is a guanine nucleotide exchange factor (GEF) that regulates cell adhesion and migration by activating the GTPase Rap1. The GEF activity of C3G is stimulated by the adaptor proteins...

Leer más

Expression of the long non-coding RNA TCL6 is associated with clinical outcome in pediatric B-cell acute lymphoblastic leukemia

31-08-2020

The reciprocal translocation t(12;21)(p13;q22)[ETV6/RUNX1] is the most frequent chromosomal rearrangement in pediatric B-cell acute lymphoblastic leukemia(B-ALL). Long non-coding RNAs (lncRNAs) play important roles in numerous diseases and they represent an...

Leer más

Evaluation of different approaches used to study membrane permeabilization by actinoporins on model lipid vesicles

30-07-2020

Release of aqueous contents from model lipid vesicles has been a standard procedure to evaluate pore formation efficiency by actinoporins, such as sticholysin II (StnII), for the last few decades...

Leer más

Socios Protectores